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Associative induction of short-term potentiation in rat hippocampus Auyeung, Anthony 1986

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ASSOCIATIVE INDUCTION OF SHORT-TERM POTENTIATION IN RAT HIPPOCAMPUS By ANTHONY AUYEUNG B. Sc. (Pharm.), The U n i v e r s i t y o f B r i t i s h Columbia, 1983  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Department o f Pharmacology & T h e r a p e u t i c s , F a c u l t y o f Medicine) We accept t h i s t h e s i s as conforming to the r e q u i r e d standard  THE UNIVERSITY OF BRITISH COLUMBIA August, 1985 ® A n t h o n y Auyeung 1986  In p r e s e n t i n g  t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of  requirements f o r an advanced degree at the  the  University  of B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make it  f r e e l y a v a i l a b l e f o r reference  and  study.  I further  agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying o f t h i s t h e s i s for  s c h o l a r l y purposes may  be granted by  department or by h i s or her  the head o f  representatives.  my  1  It i s  understood t h a t copying or p u b l i c a t i o n of t h i s t h e s i s for  f i n a n c i a l gain  s h a l l not be allowed without my  permission'.  Department of  Pharmacology and Therapeutics  The U n i v e r s i t y of B r i t i s h 1956 Main Mall Vancouver, Canada V6T 1Y3  Date  AUGUST 12 , 1986  Columbia  written  - i iABSTRACT  Tetanic can  lead  stimulation  to  long-term  o f e x c i t a t o r y a f f e r e n t pathways i n t h e hippocampus potentiation  (LTP) o f  Simultaneous t e t a n i z a t i o n o f two s e p a r a t e can  result  in associative  LTP, which  but convergent  exhibits  transmission  known p r e s y n a p t i c  a l s o o c c u r s i n the t e t a n i z e d  in  maintained  pyramidal  in - v i t r o .  cells  potentials  electrodes  placed  Population evoked  EPSPs  were  influence  of  tetanic  stimulating  electrodes  conditioning placed  population  recorded  i n a separate o f CA-^ c e l l s .  stimulation.  from  t h e CA-^ on  were  an  recorded  stimulating  with  r a t hippocampal  electrodes  Population extracellular  somata.  untetanized  cells.  Another  pathway, which  also  recording Individual  To  assess  afferent  stimulating converged  placed  excitatory  o f t h e CA-^ c e l l s . cell  from t h e  i n d i f f e r e n t pathways t o d e l i v e r  t o t h e CA^ test  using  dendrites  were p l a c e d  sectioned  responses  recorded  conditioning  stimulation  was s t i m u l a t e d  interactions leading to  and t h e a l v e u s .  (EPSP) were  at the a p i c a l  cellular  was  and were  on t r a n s v e r s e l y  stratum radiatum, stratum oriens  postsynaptic  associatively  potentiation.  Experiments were conducted  CA^  (STP)  S t u d i e s were con-  be induced  t o determine t h e n a t u r e o f p r e - and p o s t s y n a p t i c  slices  i s greater  pathway, and i s a w e l l  phenomenon a t o t h e r neuronal j u n c t i o n s .  this associative  that  pathways  Short-term p o t e n t i a t i o n  ducted t o examine i f STP i n t h e hippocampus c o u l d and  response.  afferent  a magnitude  than t h e sum o f t h e i n d i v i d u a l p o t e n t i a t i o n s . of s y n a p t i c  the postsynaptic  the  pathway, tetanic electrode  on t h e same  The t e s t pathway e i t h e r remained u n s t i m u l a t e d or  once i n c o n j u n c t i o n  with  each t e t a n i c c o n d i t i o n i n g  t r a i n of  Conditioning  tetani  duced a s s o c i a t i v e stimulation, dromic  STP  but  t h e s e c e l l s by potentiation these  paired  of  the  with  the  through  of  the  response  CA-^  at  the  alveus  cells current  STP  at  p a i r i n g s used i n t h e s e s t u d i e s ,  with  when  or  paradigm. trains  By  in  a  radiatum  in-  single  test  a  unpaired.  Anti-  depolarization  of  other  the  of  d e l i v e r i n g a number  rapid  i n a graded manner, and  found  or  i n j e c t i o n s produced the same p a t t e r n  paired/unpaired  increased of  oriens  depression  test-plus-conditioning  those  strata  t e s t response when p a i r e d  intracellular  n i t u d e of the STP resembled  of  caused  tetanization  delivered  succession,  the  junctions.  s i z e and  At  evoked a s s o c i a t i v e  the  the  mag-  time course  maximum of  STP  was  of  ten  succeeded  by  LTP. Presynaptic amount o f Schaffer en  current collateral  excitability needed  to  stimulation  afferents in with  the  resulted  test  a  of  the  an  were  These are  the  apical dendrites  of the  terminal  mechanism  assessed  antidromic  these t e r m i n a l s  i n STP  afferent  presynaptic  fire  terminals.  passant synapses w i t h  single  changes  with  action  afferent of  the  excitability. STP  found  terminals  CA-^  as  These in  the  monitoring  potential  a conditioning  t e s t EPSP, as w e l l  of  by  from that  cells.  Pairing  a parallel  spinal  are  cord  the form  t e t a n u s of  changes  the  a  other  decrease in  and  accord neuro-  muscular j u n c t i o n . The  temporal  conditioning  t e t a n u s was  the p r o b a b i l i t y of conditioning and  still  produced  overlap  STP  between the  found to be induction.  simultaneous  STP. test  v o l l e y and  the  a d e t e r m i n a n t both o f the magnitude  The  s i n g l e t e s t v o l l e y could  t e t a n u s by up to 50 msec or f o l l o w the  induce a degree of by  single test afferent  However, the and  t e t a n u s by up  greatest  conditioning  precede  and the  to 80 msec  amount of  stimulations.  STP  was These  - iv -  l e n i e n t temporal l i m i t s suggest an a l t e r e d e x c i t a b i l i t y s t a t e due and  postsynaptic  associative  STP  the and  evidence i n d i c a t e s LTP  i n the  terminal  release inal  excitability.  process f o l l o w s  process  postsynaptic  may  be  an  action  and  by  an  ent v o l l e y s .  The  hypotheses were d i s c u s s e d . has  a presynaptic  campus event. synaptic  may  be  initial  i n the  associative  terminal.  terminal  i n the  locus  simply  However, the  subliminal  I t was  concluded  of maintenance, and  that  different multiples r e s u l t s do  not  rule  l o c u s f o r the maintenance o f STP  that  of out  and  a  The  and same  LTP  possible  (Supervisor)  afferseveral  hippo-  potentiation  additional  LTP.  B h a g a v a t u l a R.  ter-  potentiation i n the  unit  the  associative  by subsequent  associative  the  between  i s unknown, but  STP  sublim-  presynaptic  excitability.  process  presyn-  presynaptic This  interactions  action potential  site  postsynaptic  a subliminal  l e a d t o enhanced t r a n s m i t t e r r e l e a s e nature of t h i s  initiating  a f f e r e n t v o l l e y to a l t e r  potential  minal through an a l t e r e d p r e s y n a p t i c i n t e r a c t i o n s could  an  The  I t i s proposed t h a t  facilitated  depolarization  a postsynaptic  hippocampus.  d e p o l a r i z a t i o n appeared t o i n t e r a c t w i t h aptic  pre-  interactions.  Taken- t o g e t h e r , for  to  Sastry  post-  -  V  -  TABLE OF CONTENTS CHAPTER  Page  ABSTRACT  ii  TABLE OF CONTENTS  iv  LIST OF TABLES  vii  LIST OF FIGURES  viii  ACKNOWLEDGEMENTS  ix  1  INTRODUCTION  1  2  REVIEW OF THE LITERATURE  4  2.1 Short-term p o t e n t i a t i o n  4  2.1.1 F a c i l i t a t i o n  6  2.1.2 Augmentation  7  2.1.3 P o s t - t e t a n i c p o t e n t i a t i o n  8  2.2 Locus of short-term p o t e n t i a t i o n  8  2.3 Mechanism of short-term p o t e n t i a t i o n  12  2.4 Ionic mechanism of short-term p o t e n t i a t i o n  14  2.5 Anatomy of the hippocampus  17  2.5.1 The dentate gyrus  20  2.5.2 The hippocampus proper  20  2.5.3 The f i e l d s of Amnion's horn  21  2.5.3.1 F i e l d CA  4  22  2.5.3.2 F i e l d CA3  22  2.5.3.3 F i e l d CA  2  22  2.5.3.4 F i e l d CA,  23  - vi -  CHAPTER  Page 2.5.4 Neuronal pathways o f t h e hippocampus  24  2.5.5 A f f e r e n t s t o t h e hippocampus  24  2.5.5.1 P e r f o r a n t Path 2.5.5.2 A f f e r e n t s t o t h e CA  24 region  26  2.5.5.3 A f f e r e n t s t o t h e CA2 r e g i o n  26  3  1  2.5.5.4 A f f e r e n t s t o t h e CA- r e g i o n L  27  2.5.6 E f f e r e n t s from t h e hippocampus  27  2.5.7  28  Interneurons  2.5.8 L o n g i t u d i n a l  a s s o c i a t i o n pathway  29  2.6 S h o r t - t e r m p o t e n t i a t i o n i n the hippocampus  29  2.7 A s s o c i a t i v e i n d u c t i o n o f p o t e n t i a t i o n : afferent cooperativity 3  30  METHODS  33  3.1 P r e p a r a t i o n  of s l i c e s  33  3.2 S l i c e bath  34  3.3 P e r f u s i o n media  37  3.4 S t i m u l a t i o n systems  38  3.5 R e c o r d i n g systems  39  3.6 A s s o c i a t i v e i n d u c t i o n o f STP  40  3.6.1 C o n d i t i o n i n g  by t e t a n i c s t i m u l a t i o n o f f i b e r s  40  3.6.2  by i n t r a c e l l u l a r d e p o l a r i z i n g p u l s e s  43  Conditioning  3.6.3 Temporal r e q u i r e m e n t s g o v e r n i n g t h e i n d u c t i o n o f STP 3.7 A s s o c i a t i v e i n d u c t i o n o f S c h a f f e r c o l l a t e r a l e x c i t a b i l i t y changes  45  terminal 45  - vii CHAPTER 4  Page  RESULTS  48  4.1 Stratum radiatum c o n d i t i o n i n g  48  4.2 Stratum o r i e n s c o n d i t i o n i n g  51  4.3 Alvear c o n d i t i o n i n g  51  4.4 I n t r a c e l l u l a r c u r r e n t i n j e c t i o n s  53  4.5 Schaffer c o l l a t e r a l terminal e x c i t a b i l i t y changes  53  4.6 Temporal requirements f o r i n d u c t i o n of STP  57  5  DISCUSSION  60  6  CONCLUSION  75  7  REFERENCES  76  - viii LIST OF TABLES TABLE 1. P o s t - c o n d i t i o n i n g p o t e n t i a t i o n induced by p a i r i n g t e t a n i c t r a i n s of the alveus with a s i n g l e s t i m u l a t i o n of the t e s t input. 2.  3.  Page  52  E f f e c t s of i n t r a c e l l u l a r l y i n j e c t e d d e p o l a r i z i n g c u r r e n t pulses on EPSPs evoked by s t i m u l a t i o n of stratum radiatum and stratum o r i e n s .  54  E f f e c t s of paired and unpaired c o n d i t i o n i n g t r a i n s on Schaffer c o l l a t e r a l terminal e x c i t a b i l i t y .  58  - ix LIST OF FIGURES FIGURE  Page  1.  Anatomical l o c a t i o n of the hippocampus in the r a t b r a i n .  19  2.  Anatomical diagram of a t r a n s v e r s e l y sectioned r a t hippocampal s l i c e showing the various a f f e r e n t , e f f e r e n t and i n t r i n s i c pathways.  25  Diagrammatic i l l u s t r a t i o n of the s l i c e bath used f o r e l e c t r o p h y s i o l o g i c a l recordings from in v i t r o hippocampal s l i c e s .  35  Experimental arrangement f o r a s s o c i a t i v e i n d u c t i o n of STP by c o n d i t i o n i n g of stratum radiatum and stratum oriens.  41  5.  Experimental arrangement f o r a s s o c i a t i v e i n d u c t i o n of STP by alvear c o n d i t i o n i n g .  42  6.  Experimental arrangement f o r a s s o c i a t i v e induction of STP by i n t r a c e l l u l a r i n j e c t i o n of d e p o l a r i z i n g c u r r e n t .  44  7.  Experimental arrangement f o r e x c i t a b i l i t y t e s t i n g of S c h a f f e r c o l l a t e r a l terminal r e g i o n s .  46  8.  A s s o c i a t i v e i n d u c t i o n of STP, LTR and the r e d u c t i o n i n the Schaffer c o l l a t e r a l terminal e x c i t a b i l i t y .  49  9.  Induction of STP and LTP by paired c o n d i t i o n i n g d e p o l a r i z a t i o n of a CAi neuron..  55  3.  4.  10. The l i m i t s of the temporal r e l a t i o n s h i p between condit i o n i n g and t e s t s t i m u l i f o r the i n d u c t i o n of associative potentiation. EPSP.  59  -  X  -  ACKNOWLEDGEMENTS  I would l i k e to thank Dr. B. R. Sastry f o r h i s ideas, guidance during the preparation o f t h i s t h e s i s .  i n s i g h t s and  Thanks a l s o go to Ms Joanne  Goh and Mr. P a t r i c k May f o r t h e i r c o n t r i b u t i o n to some of the experiments included i n t h i s t h e s i s , and f o r t h e i r support i n my moments o f s t r u g g l e . I am g r a t e f u l f o r f i n a n c i a l a s s i s t a n c e from the Medical Research Council of Canada and the U n i v e r s i t y of B r i t i s h Columbia Graduate Summer S c h o l a r s h i p .  - 1 1 INTRODUCTION The  mammalian hippocampus i s under i n t e n s i v e study  as the  c o r t i c a l s t r u c t u r e subserving l e a r n i n g and memory (Goddard, 1980; 1983).  The  (LTP)  most promising  phenomenon observed i s long-term  ( B l i s s and Gardner-Medwin, 1973;  p o t e n t i a t i o n i s induced  Bliss  and  possible  McNaughton, potentiation  Ltfmo, 1973).  Long-term  by the t e t a n i c s t i m u l a t i o n of an a f f e r e n t pathway,  leading to an enhanced p o s t - t e t a n i c response of the postsynaptic a f f e r e n t s t i m u l a t i o n ( B l i s s and Gardner-Medwin, 1971). event i s a short tetanus  cell  to  Since the i n i t i a t i n g  of several hundred m i l l i s e c o n d s , and the  ensuing  p o t e n t i a t i o n can l a s t f o r hours to days, ( B l i s s and Gardner-Medwin, 1973), LTP  appears to share c e r t a i n key  p r o p e r t i e s with  l e a r n i n g and memory and  could be the p h y s i o l o g i c a l substrate f o r both. A number of hypotheses have been advanced to e x p l a i n the mechanism behind LTP 1986;  (Baudry and  Lynch, 1980;  Skrede and Malthe-Stfrenssen,  Wigstrom and Gustafsson, mined.  The  (1978), who  1981;  Van  Harreveld  and  Malenka et- - a l : , Fifkova,  1985b), but i t s primary locus has yet to be  a s s o c i a t i v e nature  of LTP  was  described  converging  1975; deter-  by McNaughton et - -a-T;  showed that LTP can be produced in- - v i t r o by the  a c t i v a t i o n of separate produced was  C o l l i n g r i d g e , 1985;  simultaneous  a f f e r e n t pathways; the p o t e n t i a t i o n thus  greater than the sum of that produced s e p a r a t e l y by each a f -  f e r e n t pathway.  Tetanic  s t i m u l a t i o n of an a f f e r e n t pathway to f i e l d  CA^  produces LTP in t h i s area and increases the e x c i t a b i l i t y of other non-tetanized a f f e r e n t s here (Goh actions  i s unclear.  and Sastry, 1985).  The mechanism of these  I t appears t h a t a t r a n s m i t t e r  substance,  inter-  potassium  - 2 r e l e a s e d during the tetanus, or d i r e c t p a r t i c i p a t i o n of the CA-^ neuron, i s needed.  This  presynaptic  i n t e r a c t i o n with  the postsynaptic  elements  may  p o t e n t i a t i o n of  the  play a r o l e in the a s s o c i a t i v e i n d u c t i o n of LTP. Short-term p o t e n t i a t i o n postsynaptic  (STP)  response l a s t i n g up  1975a, 1975b).  is a post-tetanic to a few  minutes  (Magleby and  I t has been observed at a l l e x c i t a b l e j u n c t i o n s  i n c l u d i n g those in the hippocampus (Feng, 1941b; L l o y d , 1949; 1964).  Zengel, examined,  Gloor et - a l ; ,  At p e r i p h e r a l nerve j u n c t i o n s , STP has been shown to be a presynap-  t i c event mediated by a p o s t - t e t a n i c increase in evoked t r a n s m i t t e r (del C a s t i l l o and Katz, 1954d).  The same mechanism i s thought to mediate  STP in the hippocampus (McNaughton, 1982). accompanies LTP  (McNaughton, 1982;  shown that presynaptic  terminals  Because STP commonly precedes or  Barrionuevo and Brown, 1983) i n t e r a c t with each other  1985), i t i s p o s s i b l e that STP could a l s o be induced actions.  release  (Goh  and i t was and  Sastry,  by a s s o c i a t i v e i n t e r -  The p a r t i c i p a t i o n of the postsynaptic c e l l f o r the induction of a  r e p o r t e d l y presynaptic phenomenon, namely STP, i s c e r t a i n l y worthy of investigation. Experiments were conducted in r a t hippocampal s l i c e s i n - v i t r o . dies were designed  to examine whether STP  of CA-^ neuronal  responses could  be induced through a s s o c i a t i v e i n t e r a c t i o n s between a f f e r e n t inputs. could be thus induced,  Stu-  I f STP  then the temporal r e l a t i o n s h i p between the t e t a n i c  c o n d i t i o n i n g and a f f e r e n t t e s t s t i m u l a t i o n s would be determined. in the l i t e r a t u r e i n d i c a t e s that t e t a n i c s t i m u l a t i o n  Evidence  of the  conditioning  input causes an e x t r a c e l l u l a r negative wave near the s y n a p t i c  terminations  of a separate  a f f e r e n t t e s t pathway (Wigstrom and Gustafsson,  1985b).  This  - 3 -  wave may be i n t e r p r e t e d as a d e n d r i t i c d e p o l a r i z a t i o n , which c o u l d volved  i n the a s s o c i a t i v e induction  zation  of the postsynaptic  cell  i n d u c t i o n o f a s s o c i a t i v e LTP. ing  o f LTP.  could  result  Therefore,  depolari-  i n a condition that  favours  T h i s p o s s i b i l i t y was examined w i t h d e p o l a r i z -  currents i n j e c t e d into the postsynaptic c e l l  conditioning  direct  be i n -  t o mimic t h e e f f e c t s o f t h e  tetanus.  S h o r t - t e r m p o t e n t i a t i o n a t t h e neuromuscular j u n c t i o n and s p i n a l is  known t o be accompanied by h y p e r p o l a r i z a t i o n and d e c r e a s e d e x c i t a b i l i t y  of the presynaptic Willis, als  cord  1962).  would  terminal  ( E c c l e s and K r n j e v i c , 1959a, 1959b; Hubbard and  Intracellular  recordings  demonstrate d i r e c t l y  associative  i n d u c t i o n o f STP.  that  o f hippocampal p r e s y n a p t i c  presynaptic  However,  since  changes  occur  t h e impalement  boutons i s not y e t p o s s i b l e , t h e e x c i t a b i l i t y  of presynaptic  indirectly  employed  primary  afferent  terminology, zation zation.  assessed  using  terminal  an i n c r e a s e  of the terminal  a method changes  that  Wall  i n the spinal  i n presynaptic  cord.  excitability  termin-  during  the  of the f i n e terminals  was  i n 1958 t o measure In W a l l ' s  (1958)  indicates a depolari-  membrane, and a d e c r e a s e i n d i c a t e s a h y p e r p o l a r i -  - 4 -  2 REVIEW OF THE  The  nervous system's c a p a c i t y  LITERATURE  for f a c i l i t a t i o n  i s of g r e a t  i n t e r e s t to n e u r o b i o l o g i s t s .  ronal  will  input  a f f e c t i n some way  quent s t i m u l a t i o n of t h a t  input.  the  In g e n e r a l , postsynaptic  fleeting  high  to  a  profound  frequency r e p e t i t i v e  especially first  coined  interesting. to describe  1941b; Grumbach  and  post-synaptic  creased  presynaptic  (Bliss  and  term  a c t i v a t i o n of  a neu-  response t o  subse-  or  Eccles  the  homosynaptically  discovery  Gardner-Medwin, 1973;  come t o mean a sub-component o f  of  a post-tetanic  and  Short-term p o t e n t i a t i o n  t o date and  ( E c c l e s and 1963;  Lloyd,  i s considered  a general  in a l l excitable  phenomenon of  et a l ; , 1980).  Martin  and  Pilar,  1964;  W a l t e r s and  There i s e v i d e n c e i n the c u r r e n t  sub-components t o p o s t - t e t a n i c  STP:  (Feng, an  in-  to  in-  tens  of PTP  potentiation  Z e n g e l , 1982).  systems  synaptic  stu-  plasticity Schmidt,  Byrne, 1984;  l i t e r a t u r e to support  i) facilitation  was  1973),  K r n j e v i c , 1959a, 1959b; Feng, 1941a, 1941b; Hubbard and 1949;  are  potentiation  short-term  2.1  died  due  L0mo,  t h a t l a s t s f o r no more than s e v e r a l minutes (Magleby and  been found  as  a time course of and  to  (PTP)  PTP  long-term  Bliss  due  a tetanus  (STP)  has  range from  potentiation" to  and  stimulation)  (1953) d e f i n e d  Gardner-Medwin, 1971), which has  Short-term p o t e n t i a t i o n  a  enhancements  tetanic  enhancements due  elicited  With  response may  synaptic  "post-tetanic  1940).  action.  The  (tetanus  a l l synaptic  discharge  minutes t o days ( B l i s s and has  stimulation  Wilber,  creased  (LTP)  potentiation.  The  release  Depending on the n a t u r e o f the s t i m u l i  the e x c i t a b l e t i s s u e i n v o l v e d , the enhanced s y n a p t i c a  of t r a n s m i t t e r  Zengel three  i i ) augmentation i i i )  - 5 -  post-tetanic potentiation.  T h e i r most s a l i e n t d i f f e r e n c e s l i e i n t h e i r  res-  p e c t i v e time courses and time c o n s t a n t s o f decay (Magleby and Z e n g e l , 1982). E a r l y work on f a c i l i t a t i o n  and d e c u r a r i z a t i o n used nerve-muscle  prepa-  r a t i o n s from amphibians and mammals ( E c c l e s e t a l : , 1941; Feng, 1937, 1941a, 1941b).  Spinal  c o r d p r e p a r a t i o n s were a l s o f a v o u r e d and many c r u c i a l  find-  ings about STP were made here (Gasser and G r u n d f e s t , 1936; L l o y d , 1949; Wall and Johnson, 1958). bles  In the i s o l a t e d h e a r t , a phenomenon t h a t c l o s e l y  PTP was s t u d i e d  visual  (Hadju  and S z e n t - G y o r g y i , 1952).  Hughes  and R o s e n b l i t h ,  1957) and o l f a c t o r y  pathways showed t h a t a form o f PTP i s o p e r a t i o n a l pulse f a c i l i t a t i o n the f r o g  1939); which  from t h e  ( G e l d a r d , 1931; G r a n i t , 1955; Hughes e t a l : , 1956), a u d i t o r y  1954;  of  Evidence  was f i r s t  described  some workers  of paired-pulse assert  facilitation  fully  (NMJ)  1941b; S c h a e f e r and Haass, facilitation,  (Creager e t a l - . , 1980).  r e l a t i v e l y newly r e c o g n i z e d form o f STP i s augmentation 1976a), which has been n e i t h e r  1957)  Paired-  junction  i s frequency  i s wholly different  (Hughes,  e-t a l . ,  i n t h e s e systems.  a t t h e neuromuscular  ( E c c l e s e t a l . , 1941; Feng, 1941a,  a variant  (MacLean  resem-  elucidated  A  (Magleby and Z e n g e l ,  nor a c c e p t e d by workers i n  this f i e l d . Another observed It  new form o f p o s t - t e t a n i c p o t e n t i a t i o n  i n t h e r a t hippocampus  has a l s o  been found  1970) and mammalian  (Castellucci  characteristics,  and Atwood,  1971). 1971),  and K a n d e l , 1976; C a s t e l l u c c i e t  sympathetic ganglia  but has n o t y e t been demonstrated tinguishing  and Gardner-Medwin,  a t t h e c r u s t a c e a n NMJ (Sherman  marine m o l l u s c s e n s o r y neuron al:,  i n 1971 ( B l i s s  i s LTP, which was f i r s t  (Briggs  et- - a l : ,  a t t h e mammalian NMJ.  1983, 1985),  Regarding t h e d i s -  t h e r e i s no c o n f u s i o n o f PTP and LTP  because  - 6 -  the  latter  has  a d e c i d e d l y l o n g time  course  of  ( B l i s s and Gardner-Medwin, 1973; B l i s s and Umo, 2.1.1  ( M a l l a r t and  is a  two  component  M a r t i n , 1967).  and  i s e v i d e n t f o r up t o 600  for facilitation;  ponse  to  Bronk,  and  1947). to  and  t h a t each  provided  (Charlton  appears  (Magleby  1973).  and  This be  enhancement o f  msec i n t o  the  a tetanus  interval  1978b; Creager t w i n - p u l s e or  elementary  Z e n g e l , 1975b; M a l l a r t  impulse o f a t e t a n i c t r a i n  event and  Martin,  litation Magleby  p o t e n t i a t i o n ranged  Z e n g e l , 1975a; M a l l a r t  magnitude and time course o f each  and  Martin,  I t was  1967).  two  facilitation 1980)  has  been  found  component  response;  the  faci-  Assuming  that  the  impulse were the same, M a l l a r t and M a r t i n  c o n s t a n t s o f 35  250  determined  (Magleby, 1973a, 1973b;  i n the f r o g  and  facilitation  adds a l i n e a r  (1967) were a b l e t o d e s c r i b e f a c i l i t a t i o n msec  than  Larrabee  from 5 0 % f o r f r e q u e n c y  t o about 100% f o r p a i r e d - p u l s e f a c i l i t a t i o n and  more  facilitation  frequency  1967).  of s t i m u l a t i o n  the r e s -  et- - a l ; , 1980;  paired-pulse  behind  1973a,  i s not e s s e n -  i s not  to the base r a t e o f t r a n s m i t t e r r e l e a s e and t o the f a c i l i t a t e d magnitude o f t h e aggregate  release  (Magleby,  i m p u l s e can f a c i l i t a t e  intervening  Bittner,  is called  the  transmitter  Indeed, t e t a n i c s t i m u l a t i o n  a s i n g l e antecedent  a stimulus,  50-100 msec. and  t o many weeks  I t i s p r e s e n t i m m e d i a t e l y upon the onset o f a  1973b; M a l l a r t and M a r t i n , 1967). tial  minutes  Facilitation  Facilitation  tetanus  30  msec.  This  in rabbit  NMJ  with  two  decay  component c h a r a c t e r i s t i c  sympathetic  ganglia  (Zengel  of  et- - a l . - ,  and r a t hippocampus (Creager e t a l ; , 1980). Katz  and  Miledi  (1968) showed  paired-pulse f a c i l i t a t i o n  and  the  frequency  c a l c i u m ( C a ) dependence o f + +  facilitation  and  used  these  both  pheno-  - 7 -  mena  to support  release. dual  Although  Ca  Ca  especially  may  Ca  facilitation  depend  theory  + +  established  that  paired-pulse —  transmitter  both  share  to resi-  a common  active  F o r example, i n t h e s q u i d g i a n t  on t h e presence and B i t t n e r ,  of f a c i l i t a t e d  and PTP have been a t t r i b u t e d  e t - a l ; , 1973).  (Charlton  + +  facilitation  was  both  (Landau  + +  facilitation  of  residual  , i t i s not f i r m l y  pool o f C a  residual  their  of a C a  1978a).  can be evoked  current  + +  Furthermore,  rather  facilitation  i n d e p e n d e n t l y o f PTP.  and i t s time c o u r s e remained  t h e same even  axon, than —  The degree  i f facilitation  induced d u r i n g t h e maximal phase o f PTP (Creager e t - a l - ; , 1980; Magleby,  1973a). 2.1.2  Augmentation  Augmentation of  i s differentiated  i t s time c o u r s e and decay  the work on augmentation  from f a c i l i t a t i o n  c o n s t a n t (Magleby  and PTP on t h e b a s i s  and Z e n g e l , 1976b).  Most o f  has been done by Magleby and Zengel on t h e f r o g NMJ ++  blocked  with  high  posed  this  decay  constant  PTP.  extracellular  magnesium  ).  In 1 9 7 5 ( a ) ,  they  pro-  i n t e r m e d i a t e phase o f s y n a p t i c enhancement on t h e s t r e n g t h o f a o f 7 seconds:  longer  than  facilitation  and s h o r t e r  than  I n c r e a s i n g t h e number o f impulses i n t h e t e t a n u s added l i n e a r l y t o t h e  s i z e o f t h e augmentation cant e x t e n t (Magleby  w i t h o u t changing t h e time c o n s t a n t t o any s i g n i f i -  and Z e n g e l , 1976a).  on f a c i l i t a t i o n  crease  i n q u a n t a l c o n t e n t , m, t o account  Z e n g e l , 1982; Zengel their  and p o t e n t i a t i o n  A m u l t i p l i c a t i v e e f f e c t o f augmen-  tation  in  (Mg  and Magleby, 1982).  various studies  L a r r a b e e and Bronk  that  was proposed,  as was a common i n -  f o r t h e enhancement Magleby and Zengel  augmentation  was p r e s e n t  (Magleby and  have  suggested  i n the r e s u l t s  (1947), L i l e y (1956) and Landau e t - al.-(1973).  of  Notwith-  -  standing  the common  differential lease  effects  (Zengel  existence  dependence  o f augmentation  Post-tetanic  700%  + +  ,  different  1977, 1980).  is still  divalent  increases  have  in transmitter r e -  Corroborating  limited  cations  evidence  and, t h e r e f o r e ,  f o r the  t h e concept i s  accepted.  2.1.3 P o s t - t e t a n i c  control  Ca  -  on t h e s t i m u l u s - i n d u c e d  and Magleby,  not y e t g e n e r a l l y  on  8  potentiation  potentiation  can range from 3 minutes  and up t o 500% o f  i n the f r o g NMJ (Magleby and Z e n g e l , 1975a) t o 10 minutes and over  of control  i n the avian  ciliary  ganglion  ( M a l l a r t and M a r t i n ,  1967).  There had been e a r l y hopes t h a t PTP would prove t o be t h e e l u s i v e l i n k ween p h y s i o l o g y as  learning  substrate 1979).  and p s y c h o l o g y as t h e s u b s t r a t e  and memory  has s h i f t e d  (Hughes, 1958).  Since  t o LTP (McNaughton  f o r such  dynamic  then, the focus  et a l 1 9 7 8 ;  Levy  Much o f t h e work on STP has a c t u a l l y been d i r e c t e d  fore, the following sections  on t h e v a r i o u s  bet-  processes  f o r such and  a  Steward,  a t PTP;  there-  a s p e c t s of STP by n e c e s s i t y  deal  l a r g e l y w i t h PTP. 2.2  Locus of s h o r t - t e r m p o t e n t i a t i o n In  tension  1858, S c h i f f r e p o r t e d i n the f r o g  on t h e p o s t - t e t a n i c  gastrocnemius-sciatic  potentiation  preparation.  Boehm  s e r v e d a temporary d e c u r a r i z i n g e f f e c t o f t e t a n i c s t i m u l a t i o n curarized  sciatic-gastrocnemius  facilitating of  another  preparation.  In 1912, Forbes  of twitch (1894) ob-  i n the h e a v i l y reported  e f f e c t o f a t e t a n u s t o one nerve on t h e p o s t - t e t a n i c adjacent  nerve.  Feng e t • -a/h  (1938) d e s c r i b e d  the  response  the p o s t - t e t a n i c  r e p e t i t i v e d i s c h a r g e o f t h e f r o g neuromuscular j u n c t i o n ; however, t h e f a c i litating  e f f e c t co-occurs with  a prevailing inhibition  (depression).  Other  - 9 workers found that a few t e t a n i of short duration block, while E u l e r , 1938).  a neuromuscular  a d d i t i o n a l t e t a n i could remove t h i s blockade (Brown and  von  There was much debate on the locus of t h i s PTP; some workers  maintained that  i t was  a phenomenon of the muscle c o n t r a c t i l e elements  (Walker, 1947), since d i r e c t s t i m u l a t i o n produce PTP.  induced  of c u r a r i z e d muscle appeared  to  However, other workers found that d i r e c t s t i m u l a t i o n did not  produce PTP (Guttman e t a l : , 1937), and concluded  that PTP was an  end-plate  Meanwhile, i n the i s o l a t e d f e l i n e dorsal r o o t , Gasser and  Grundfest  event at the  NMJ.  (1936) made d e t a i l e d observations  of p o s t - t e t a n i c changes which  correspond  to the same changes seen in f r o g nerve (Gasser and Graham, 1932).  They des-  c r i b e d two phases of p o s t - t e t a n i c h y p e r p o l a r i z a t i o n , a short f i r s t phase of several msec duration followed by a depression, and a prolonged  second phase  of h y p e r p o l a r i z a t i o n whose amplitude and duration were dependent upon preceding + 0.6  tetanus:  to 0.7  Grundfest,  mV,  1936).  (presynaptic  " A f t e r a maximal tetanus and  the duration  Moreover, the  spike) was  P o t e n t i a t i o n was  antidromic "prolonged  postganglionic  post-tetanic  also g r e a t l y enhanced.  reported what they c a l l e d "prolonged lion.  of 30 sec, the p o t e n t i a l i s  more than four minutes." (Gasser associated  spike  Larrabee and  and  potential  Bronk (1938)  f a c i l i t a t i o n " in the cat s t e l l a t e gang-  observed with tetanus,  the  preganglionic  leading  the  tetanus,  authors  to  but not  with  conclude  that  f a c i l i t a t i o n " must occur p r e g a n g l i o n i c a l l y .  Woolsey and Larrabee (1940) t e t a n i z e d the f e l i n e dorsal root and were able to show the same two phases of h y p e r p o l a r i z a t i o n , confirming creases in the frequency  and duration of the tetanus  lead  that i n -  to increases in  - 10 both amplitude  and duration of the second h y p e r p o l a r i z a t i o n .  A concomitant  f a c i l i t a t i o n of the evoked i p s i l a t e r a l v e n t r a l root discharge l a s t e d f o r the duration of the second prolonged charge could root.  not  In 1947,  be  induced  Larrabee  t i o n and were convinced  hyperpolarization.  f o l l o w i n g antidromic  t e t a n i to the  that a p r e g a n g l i o n i c s i t e was  converging  facilita-  the locus of change.  c e l l s as well as nerve trunks,  that the l a r g e s t p o s t - t e t a n i c g a n g l i o n i c response was  more ganglion c e l l s responding  dis-  ventral  and Bronk again examined t h i s prolonged  By r e c o r d i n g from s i n g l e ganglion found  This f a c i l i t a t e d  (Larrabee and Bronk, 1947).  i t was  the r e s u l t of  Experiments with  nerve trunks showed that t e t a n i z a t i o n of one p r e g a n g l i o n i c  input  a c t u a l l y r e s u l t s i n decreased e x c i t a b i l i t y of the p o s t g a n g l i o n i c c e l l .  This  same decrease  in e x c i t a b i l i t y extended to responses  c h o l i n e and l a s t e d f o r about 1 minute.  to exogenous a c e t y l -  Other workers have s i n c e  the decreased e x c i t a b i l i t y as a necessary r e s u l t of a tetanus B i t t n e r , 1978b; Martin and P i l a r , 1964).  disputed  (Charlton  In a d d i t i o n , Larrabee  and  and  Bronk  (1947) described paired-pulse f a c i l i t a t i o n without naming i t : a s i n g l e preg a n g l i o n i c v o l l e y was s u f f i c i e n t to p o t e n t i a t e the response to a  succeeding  v o l l e y , much as Feng (1940) had shown i n the NMJ of the toad. Lloyd  (1949) f u r t h e r advanced the  causal  r e l a t i o n s h i p between  p o s t - t e t a n i c p o s i t i v e a f t e r p o t e n t i a l ( h y p e r p o l a r i z a t i o n ) and PTP. the p a r a l l e l s in the amplitude  and  time course  between the  He  the noted  post-tetanic  a f f e r e n t impulse, the period of h y p e r p o l a r i z a t i o n and the p o t e n t i a t e d monosynaptic r e f l e x . He proposed a presynaptic b a s i s f o r PTP whereby a postt e t a n i c h y p e r p o l a r i z a t i o n r e s u l t s in a l a r g e r presynaptic spike that i n turn leads to greater t r a n s m i t t e r r e l e a s e .  E c c l e s and R a i l (1951) argued that a  - 11 -  tetanus of  the  o f 30-300 v o l l e y s i s f o l l o w e d synaptic  time when  p o t e n t i a l , which  the  presynaptic  and  Johnson  by  occurs  spike  a brief  post-tetanic potentiation  w i t h i n 200  msec p o s t - t e t a n u s  i s a c t u a l l y smaller  than  the  at  a  pre-tetanus  control. Wall d i r e c t l y by synaptic  t e s t i n g the  reflex  excitability  loop  of  the  the magnitude and (1949),  Wall  period: the  (Wall,  1958).  afferent  fiber  a delay before  the  r e s u l t s and  presynaptic  hypothesis  in afferent fibers  found  terminal  a  marked  of  rent  Like Eccles  and  Rail  i n the  A l t e r n a t e l y , the  f e r e n t impulses presynaptic  (del C a s t i l l o  spike  thus  excitability  terminals  axon  (Takeuchi  and  generated  Schmidt, 1963)  and  supported  inducing  of  height  and  cellular  virtue  end-plate  recordings  will  were indeed  almost  immediate-  hyperpolarized,  1962)  a  the  nerve  than  and  desynchronize  that  of  the  mammalian  NMJ  af-  of  the  control.  (Hubbard and  and  Schmidt  s p i k e s i z e are c a p a b l e of  r e l a t i o n s h i p between  of  affe-  the  height  F u r t h e r m o r e , Hubbard  amplitude.  terminal  post-  K r n j e v i c , 1959a, 1959b), s q u i d  in presynaptic  logarithmic  they  i n some branches of the  less  ( E c c l e s and  p o t e n t i a l (epp) at  be  these f i n d i n g s . increases  by  Lloyd  immediate p o s t - t e t a n i c  K a t z , 1954d) such t h a t the  Takeuchi,  (1963) showed t h a t small PTP  the with  (1951) and  maximized  h y p e r p o l a r i z a t i o n can  Subsequent s t u d i e s i n s p i n a l cord giant  in  the p o t e n t i a t e d r e f l e x maximized, whereas  i s ' s u f f i c i e n t to produce anodal b l o c k  fibers.  a mono-  decrease  suggested t h a t the i n t e n s i t y of t h i s h y p e r p o l a r i z a t i o n i m m e d i a t e l y tetanus  more  arborizations coincident  a discrepancy  in afferent terminal  that  changes They  of PTP.  Johnson found  t h e r e was  Given  excitability  duration  and  decrease  ly.  (1958) examined L l o y d ' s  On avian  the  the  spike  hand,  intra-  ganglia  showed  other  ciliary  - 12 -  n e i t h e r changes i n p r e s y n a p t i c membrane p o t e n t i a l nor the  presynaptic  Pilar,  spike during  1964).  In s p i t e o f these  i s t h a t f a c i l i t a t i o n and PTP 2.3  paired-pulse  facilitation  and  PTP  (Martin  c o n f l i c t i n g r e s u l t s , the general  are p r e s y n a p t i c  of and  consensus  events.  Mechanism o f - s h o r t - t e r m - p o t e n t i a t i o n The  r e l a t i o n s h i p between p o s t - t e t a n i c h y p e r p o l a r i z a t i o n and  postsynaptic In 1934, indeed  response r e s t e d upon the  Dale and  Feldberg  the chemical  Continued chemical  efforts  first  responsible for synatpic transmission by  various  transmission  until  Eccles  endplate  workers  and  The  and  Katz  1954.  observations  of  spontaneous  stimulating amplitude  i n high  the  chemical  advanced  Drawing  del C a s t i l l o and  bathed  and  del  from  their  quantal  minimal  size,  their  idea  Kuffler, not  of  1948), laid  supported  Fatt  and  miniature  theory  Katz'  end-plate  to and  chemical  neuromuscular  (1952a,  1952b; (mepp)  1953) at  the  Katz observed i n the i s o l a t e d nerve-muscle p r e p a -  magnesium  and  of  potentials  (Mg ) ++  and/  or  low  nerve r e s u l t e d i n epps whose minimal  Castillo  1942;  the  NMJ.  anticholinesterases  evidence  o f spontaneous mepps ( d e l C a s t i l l o  tantly,  to  t r a n s m i s s i o n was  (1949) o f  was  ACh.  in  ration  transmission.  at mammalian  support  et - -al:,  overwhelming  transmission  f r o g NMJ,  Eccles  MacFarlane's study  t r a n s m i s s i o n mediated by Castillo  l e n t growing  ( E c c l e s , 1948;  potential.  Del  e l u c i d a t i o n of synaptic  increased  gave e v i d e n c e t h a t a c e t y l c h o l i n e (ACh)  but the debate between e l e c t r i c a l rest  i n c r e a s e d amplitude  Katz  amplitudes  m u l t i p l e s o f the mean mepp.  noted could  that be  where closely  Thus: m x mepp =  and  epp  calcium size  (Ca ), + +  equals  the  that mean  K a t z , 1954b).  Most impor-  the  not  epps were  predicted  by  of  the  whole number  - 13 -  where mepp i s the elementary  u n i t o f t r a n s m i t t e r and  the number o f such u n i t s per epp. product  Quantal  content  quantal  content  (m)  i s f u r t h e r d e f i n e d as  o f the number o f quanta a v a i l a b l e f o r r e l e a s e , n,  and  the  is the  probabi-  l i t y o f r e l e a s e , p; t h e r e f o r e , t h e mean q u a n t a l c o n t e n t i s : m = n x p When the p r e s y n a p t i c t e r m i n a l i s h y p e r p o l a r i z e d to or beyond a c r i t i c al  l e v e l , t h e r e i s an  increased frequency  of  spontaneous mepps i n the  form  o f b u r s t s , but the q u a n t a l u n i t o f these mepps i s not i n c r e a s e d ( d e l C a s t i l l o and of  K a t z , 1954d). the  epps  During  such  a p e r i o d o f h y p e r p o l a r i z a t i o n , the  i n c r e a s e d , sometimes f o r  hyperpolarization.  In a d d i t i o n ,  a  evoked  few  seconds  epps  showed  t h a t i s a t t r i b u t a b l e to i n c r e a s e d q u a n t a l c o n t e n t . (1953) had concluded  t h a t PTP  after an  the  amplitude  end  increased  of  the  amplitude  E a r l i e r , L i l e y and  North  i s a nerve t e r m i n a l phenomenon t h a t i s mediat-  ed by an i n c r e a s e d evoked r e l e a s e o f ACh;  increased end-plate  sensitivity  to  the n e u r o t r a n s m i t t e r appeared t o have p l a y e d v e r y l i t t l e p a r t . Another o b s e r v a t i o n e x p l a i n e d by the q u a n t a l mechanism i s the p o s t tetanic 1951;  depression  Liley  transmitter  and  that occurs  North,  release  after  1953).  i s not  Under  impaired  c o n c e n t r a t i o n s of M g , a t e t a n u s ++  an  intense tetanus  c o n d i t i o n s of  by  agents  o f 500  normal  such  volleys  ( E c c l e s and  as  ed by  a p e r i o d of PTP.  t e r r e l e a s e , no 1941b). tetanus  depression  L i l e y and to  However, i n high  account  North for  i s observed  depression.  extracellular  i s f o l l o w e d by  , which  (del C a s t i l l o  (1953) suggested this  Mg  r e l e a s e , when  high  s i o n l a s t i n g s e v e r a l hundred msec ( E c c l e s and R a i l , 1951).  a  depres-  This i s  succeed-  diminishes  and  Rail,  transmit-  K a t z , 1954c; Feng,  a d e p l e t i o n o f quanta d u r i n g I t appears  that  no  the  significant  - 14 -  changes i n p o c c u r s  during depression  in  and  n  (del C a s t i l l o  showed  that  Katz,  facilitation  while there  1954c).  can  be  Del  i s an a s s o c i a t e d decrease  Castillo  accounted  for  and  by  Katz  an  (1954c)  increased  also  quantal  content. To  f u r t h e r e x p l a i n the q u a n t a l  necessary  to  invoke  Quastel's  (1965) f u n c t i o n a l model  the evidence  the  presented  idea  of  by o t h e r s  events  during  and  post-tetanus,  transmitter mobilization. of  i t is  Elmqvist  t r a n s m i t t e r m o b i l i z a t i o n concurs  (Hubbard, 1963;  Hubbard and  Willis,  and with  1962).  In t h i s model, the number o f r e a d i l y a v a i l a b l e quanta i n the nerve t e r m i n a l is relatively mitter  small.  During  i s q u i c k l y depleted  a high  (Otsuka  intensity  e t a l ; , 1962).  m i t t e r , presumably not  i n the form of  ized  available pool.  into  constant  the to  readily  restore  d e p l e t i o n and  n  at  the  to  t o the i n t e n s i t y  peak  (del  2.4  Castillo  1936;  Takeuchi  and  Katz,  the amplitude  to  number of  and  impulses  of t r a n s -  be  4-5  be  increases with  1954c; E c c l e s and  the  Rail,  L l o y d , 1952,  Early  work  potassium  on  neuromuscular  (K ) +  had  the  and  L i , 1941).  1951;  the  preparations  Other  and  of  time This  explains  is  propor-  the  latency  the  tetanus  Feng, 1937;  Feng  et  1959).  same f a c i l i t a t o r y  s t i m u l a t i o n (Feldberg  tetanus,  intensity  mobil-  seconds.  d u r a t i o n o f PTP i n the  -mechanism-of-short-term-potentiation  Feng  A second pool  (1958) e s t i m a t e s  p o s t - t e t a n i c NMJ  Gasser and Graham, 1932;  tetanic  of t r a n s -  packaged q u a n t a , must then  Ionic  external as  and  potentiation actually  a l ; , 1939;  pool  subsequent r e s t o r a t i o n of quanta a t the t e r m i n a l thus  the o b s e r v a t i o n t h a t , although tional  tetanus, t h i s  suggested and  that  increased  decurarizing effects  V a r t i a i n e n , 1934;  i n v e s t i g a t o r s proposed  Wilson that  and an  Wright, increased  - 15 extracellular  K  was r e s p o n s i b l e  +  Grumbach and W i l b e r , raised  external  K  1940; Walker,  cannot  +  (Feng  K  leads  +  and L i , 1941).  and M o r i s o n , 1937;  Feng e t - al-;  (1939)  stated  that  s i n c e PTP i n t h e presence o f  potas-  induced by t e t a n i c s t i m u l a t i o n a l o n e .  Fur-  t o depression  Liley  (Rosenblueth  1948).  be i n v o l v e d  sium c h l o r i d e i s l e s s than t h a t t h e r m o r e , high  f o r PTP  o f t h e NMJ r a t h e r  and North  (1953)  proposed  increased  release  than  potentiation  another  perspective:  as i t was known t h a t  t e t a n u s causes  perhaps t h e c r i t e r i o n  f o r p o t e n t i a t i o n i s an apparent decrease o f i n t r a c e l -  l u l a r K , which can be mimicked by r a i s i n g e x t e r n a l +  o f both ACh and K , +  K . +  The work on potassium proved i n c o n c l u s i v e , and w i t h t h e e l u c i d a t i o n o f the q u a n t a l to  mechanism o f t r a n s m i t t e r r e l e a s e , t h e f o c u s o f a t t e n t i o n s h i f t e d  calcium.  istic'  I t was  effects  known  a t t h e NMJ:  blocked  by high  raising  extracellular Ca  sence  e x t r a c e l l u l a r Mg ; ++  insufficient  and M g  + +  t o cause  this  nerve  have  depolarization transmitter  mutually  and nerve  block  could  o f t h e nerve  release  (Katz  'antagontransmission  be r e l i e v e d by  and Engbaek, 1954).  i f t h e d e p o l a r i z a t i o n was c o u p l e d w i t h  In t h e ab-  terminal  was i n  and M i l e d i , 1967).  an i o n t o p h o r e t i c  pulse  of C a  t o t h e nerve t e r m i n a l s , then t r a n s m i t t e r r e l e a s e was evoked  and M i l e d i , 1967). requires  + +  can be reduced  (del C a s t i l l o  + +  + +  localized  45  Ca  epps  of extracellular C a ,  itself But  that  Ca . + +  + +  (Katz  Hence, t r a n s m i t t e r r e l e a s e o r m u l t i p l i c a t i o n o f r e l e a s e  Studies  of C a  + +  uptake  i n the squid  giant  axon  using  ++ Ca  Aequorin  showed  stimulus-dependent  loaded s q u i d  axons  uptake  emit l i g h t  (Hodgkin  and  Keynes,  upon d e p o l a r i z a t i o n , showing  conductance whose time c o u r s e i s u n a f f e c t e d  by t e t r o d o t o x i n  ammonium (Baker e t a l ; , 1971; L I i n a s e t - a l ; , 1972).  1957). a Ca  + +  and t e t r a e t h y l -  - 16 E x a c t l y how calcium e f f e c t s t r a n s m i t t e r r e l e a s e i s unknown. been proposed that a C a  + +  I t has  a c t i v a t e d complex, CaX, somehow increases the  p r o b a b i l i t y o f t r a n s m i t t e r r e l e a s e at the terminal membrane ( d e l C a s t i l l o and Katz, 1954a).  Assuming that r e l e a s e i s p r o p o r t i o n a l to the f o u r t h power  of CaX (Dodge and Rahamimoff, 1967), Katz and M i l e d i (1968) advanced the r e s i d u a l calcium theory o f f a c i l i t a t i o n at the f r o g NMJ. the t r a n s i e n t increase i n C a to an i n f l u x o f C a  + +  They proposed that  conductance during the d e p o l a r i z a t i o n ,leads  + +  that combines with X to form the a c t i v e complex CaX.  It i s i n t e r e s t i n g t o note that elevated l e v e l s o f i n t r a c e l l u l a r C a s i s t beyond the duration 1981). terval will  of stimulus-evoked  I f a subsequent stimulus  release  ( M i l e d i and  Parker,  invades the terminal w i t h i n a c e r t a i n i n -  a f t e r the f i r s t stimulus, then the r e s i d u a l C a be augmented by another  per-  + +  influx of C a . + +  + +  i n the terminal  The t r a n s m i t t e r thus r e -  leased w i l l be p r o p o r t i o n a l to the sum o f the i n t r a c e l l u l a r C a  (or CaX)  + +  r a i s e d t o the f o u r t h power. A l t e r n a t e mechanisms f o r PTP i n v o l v i n g sodium (Na ) c u r r e n t s or i t s +  accumulation  i n the presynaptic terminal are l a r g e l y unsupported.  Post-  t e t a n i c p o t e n t i a t i o n o f the epp was i n d u c i b l e when a l l external  Na  +  was  replaced by i s o t o n i c calcium c h l o r i d e , and when voltage s e n s i t i v e N a chan+  nels were blocked Na  +  plays  by t e t r o d o t o x i n (Weinreich,  a supportive  1971).  I t i s p o s s i b l e that  role, indirectly increasing i n t r a c e l l u l a r  calcium  ions by competing at a common i o n b u f f e r i n g system or f o r a l i m i t e d energy source  f o r extrusion  ( B i r k s and Cohen, 1968; Rahamimoff e t - - a l ; ,  1980).  I n t e r e s t i n g l y , M i s l e r and Hurlbut (1983) were able to induce PTP at the f r o g NMJ i n the absence o f e x t r a c e l l u l a r C a . + +  I n t r a c e l l u l a r recordings  showed  - 17 that PTP o f mepp frequency and epp s i z e can be induced with r e p e t i t i v e s t i m u l a t i o n i n 0 mM C a the bathing medium 1983).  + +  and 1-2 mM EGTA, provided that C a immediately  after  These authors a l s o suggest a Na  the tetanus +  dependent  + +  (Misler  i s r e s t o r e d to and Hurlbut,  mechanism f o r PTP, but  t h e i r s p e c u l a t i o n remains u n s u b s t a n t i a t e d . 2.5  Anatomy-of-the-hi ppocampus The hippocampus i s part of the o l d e s t c o r t i c a l s t r u c t u r e i n the mam-  malian b r a i n . During embryonic development,  c e l l s from the mantle l a y e r at  the r o s t r a l end o f the neural tube p r o l i f e r a t e .  This c e l l mass migrates  beyond the marginal l a y e r , e v e n t u a l l y surrounding the neural tube t o become the c o r t i c a l grey matter ( C r e l i n , 1974).  During p r o l i f e r a t i o n and migra-  t i o n , the i s o c o r t e x separates from the mantle l a y e r to form the neocortex; the remaining a l l o c o r t e x , which i s the more p r i m i t i v e , maintains i t s a t t a c h ment to the mantle l a y e r ( F i l i m i n o f f , 1947).  There i s a l s o a t r a n s i t i o n a l  cortex, c a l l e d the p e r i a l l o c o r t e x , t h a t d i f f e r s  i n c y t o a r c h i t e c t u r e from  both neocortex and a l l o c o r t e x (Brodmann, 1909). In mammals, the a l l o c o r t e x i s found mostly around the brainstem i n a c o r t i c a l c o n v o l u t i o n that Broca (1878) c a l l e d the l i m b i c lobe.  This true  a l l o c o r t e x i s subdivided i n t o paleocortex and a r e h i c o r t e x . The former comp r i s e s the o l f a c t o r y bulb and a s s o c i a t e d s t r u c t u r e s ; the l a t t e r the subiculum, the hippocampus proper (fascia  d e n t a t a ) , precommissural  campus (Schwerdtfeger, 1984).  (Amnion's  hippocampus  comprises  horn), the dentate  and supracommissural  gyrus hippo-  The obvious presence o f o l f a c t o r y pathways  led to the name "rhinencephalon", f o r i t was b e l i e v e d that o l f a c t i o n was the l i m b i c lobe's only f u n c t i o n ( K o l l i k e r , 1896; Schaefer, 1898).  Later work on  - 18 the l i m b i c system (MacLean, 1952; Papez, 1937) d i s p e l l e d the s i n g l e f u n c t i o n role f o r this o l d cortex. The hippocampal formation c o n s i s t s o f the p e r i a l l o c o r t i c a l p r e s u b i c u lum, area r e t r o s p h e n i a l i s e, the parasubiculum and the e n t o r h i n a l region ( C h r o n i s t e r and White, 1975).  Of the remaining a r c h i c o r t e x , o n l y Amnion's  horn and the f a s c i a dentata w i l l will  be f u r t h e r  be considered as the hippocampus.  d e f i n e d so t h a t "hippocampus  proper" w i l l  This  denote  only  Amnion's horn, e x c l u d i n g the subiculum. The hippocampus  is bilaterally  symmetrical, shaped  cashew nuts (Green, 1964; T e y l e r and DiScenna, 1984).  like  commas or  They l i e d i r e c t l y  under the neocortex with t h e i r d o r s a l ends connected by the commissural fiber tract.  The body o f the hippocampus  i s pressed a g a i n s t the medial wall  of the i n f e r i o r horn of the l a t e r a l v e n t r i c l e . hippocampus  The v e n t r a l t a i l  o f the  f o l l o w s the l a t e r a l v e n t r i c l e toward the corpus callosum ( F i g u r e  1). Each hippocampus  c o n s i s t s of two i n t e r d i g i t a t i n g a r c h i c o r t i c a l p a r t s ,  the cornu ammonis (CA) and the f a s c i a dentata (FD). of the hippocampus  The v e n t r i c u l a r s u r f a c e  i s covered by a white f i b e r l a y e r , the a l v e u s .  These  f i b e r s are composed mainly o f axons from c e l l s o f the CA f i e l d s and converge to form the f i m b r i a on the medial s u r f a c e o f the hippocampus DiScenna, 1984).  The c e l l s o f the hippocampus  (Teyler and  are i n three b a s i c l a y e r s :  molecular, p r i n c i p l e , and polimorph (Lorente de No, 1934). ' T h i s i s i n cont r a s t to the s i x (Brodmann, 1909) or seven (Rose, 1926) l a y e r s o f the neocortex.  I t i s i n t e r e s t i n g to note t h a t Ramon y Cajal (1893) had a c t u a l l y  described Amnion's horn as a seven layered c o r t i c a l s t r u c t u r e .  - 19 -  Figure 1 Anatomical l o c a t i o n o f the hippocampus i n the r a t b r a i n . The top diagram shows the p o s i t i o n o f the hippocampus with r e s p e c t to the r e s t o f the b r a i n and the bottom diagram i l l u s t r a t e s the various s u b f i e l d s o f a t r a n s verse s e c t i o n o f the hippocampus. Hip. f i s . - hippocampal f i s s u r e I n f r a - i n f r a p y r a m i d a l blade o f the dentate granule cell layer Supra - suprapyramidal blade o f the dentate granule cell layer  - 20 2.5.1  The-dentate-gyrus  The dentate gyrus, as i t s name suggests, i s a V or U-shaped f o l d of cortex t h a t caps the t h i n terminal edge of the hippocampus proper.  The  p r i n c i p l e c e l l s are the granule c e l l s (Ramon y C a j a l , 1893) found i n a l a y e r 5-10 c e l l s deep, the stratum granulosum.  These granule c e l l s send d e n d r i t e s  that p o i n t towards the dentate h i l u s as well as d e n d r i t e s that p o i n t to the ventricular surface.  The granule c e l l  l a y e r and converge about the h i l u s . this  layer,  axons course through the  polymorph  In a d d i t i o n to polymorphic c e l l s i n  there are i n h i b i t o r y basket c e l l s , which  synapse  with many  granule c e l l s through a supragranular axon plexus (Ramon y C a j a l ,  1893).  Between the suprapyramidal and i n f r a p y r a m i d a l blades of the FD i s the h i l u s , a transition  region of polymorphic  (Lorente de No, 1934).  cells  and  modified pyramidal  These pyramidal c e l l s are considered part of the  t a i l of hippocampus proper and c o n s t i t u t e s the f i e l d CA^ 1934).  cells  (Lorente de  No,  Because the polymorphic l a y e r s of both CA and FD are c o n f l u e n t , the  whole r e g i o n demarcated by an imaginary l i n e drawn between the ends of the stratum granulosm  has been c o l l e c t i v e l y l a b e l l e d area dentata ( B l a c k s t a d ,  1956; T e y l e r and DiScenna, 1984). morphology  does  not  support  this  However, c a r e f u l examination of the c y t o classification  (Ramon y  Cajal,  1893;  Lorente de No, 1934). 2.5.2  The-hippocampus-proper  The t h i n edge of the cornu ammonis terminates i n the h i l u s of the f a s c i a dentata.  The t r a n s i t i o n a l pyramidal c e l l s from the h i l u s g r a d u a l l y  change to the pyramidal c e l l s of area CA^ (Lorente de No, 1934). the CA/,  field  is difficult  to d e t e c t ( B l a c k s t a d , 1956;  Although  C h r o n i s t e r and  - 21 White, 1975), the cascade o f pyramidal c e l l s from CA^ t o form the stratum pyramidale o f the hippocampus proper i s e a s i l y d i s c e r n i b l e .  These pyramidal  c e l l s are o r i e n t e d with t h e i r a p i c a l d e n d r i t e s pointed towards the center of the hippocampus a t the b l i n d end of the hippocampal  fissure.  The s t r a t i f i c a t i o n at the cornu ammonis i s more i n v o l v e d than that i n the dentate gyrus.  A l a y e r o f axon f i b e r s , the a l v e u s , l i e s next to the  surface at the l a t e r a l v e n t r i c l e . of polymorphic  Adjacent to the alveus i s a f i b e r plexus  c e l l s , the stratum o r i e n s .  The next two l a y e r s are the  stratum pyramidale and the stratum lucidum, the l a t t e r l a y e r i s r a t h e r poorl y d e f i n e d i n the rodent hippocampus and i s considered as one with the stratum pyramidale (Lorente de No, 1934).  The same a p p l i e s to the dense  f i b e r plexus o f the stratum radiatum and the stratum lacunosum, c o l l e c t i v e l y as stratum radiatum (Lorente de No, 1934).  considered  Next t o the stratum  radiatum i s the stratum moleculare (Lorente de No, 1934).  The boundaries o f  s t r a t a radiatum and o r i e n s mark the terminus of the hippocampus proper at the h i l u s . abrupt  The boundary at the s u b i c u l a r end i s very s h a r p l y d e f i n e d by the  t e r m i n a t i o n of the stratum  pyramidale  in field  CA,  1975; B l a c k s t a d , 1956; Ramon y C a j a l , 1893; Lorente de No, 1934).  (Angevine, Because  of anatomical and p h y s i o l o g i c a l d i f f e r e n c e , the hippocampus proper i s d i v i ded i n t o s e v e r a l f i e l d s and s u b f i e l d s , each denoted by the l e t t e r s CA and a numerical or alpha-numerical term (Lorente de No, 1934). 2.5.3 The - f i elds of Ammon's- horn F i g u r e 1 i l l u s t r a t e s the d i f f e r e n t s u b f i e l d s of Amnion's horn and the dentate gyrus i n a t r a n s v e r s e s e c t i o n o f the r a t hippocampus.  - 22 2.5.3.1 F i e l d - - G A / | A s mentioned  above, t h i s poorly  demarcated  zone c o n s i s t s of t r a n s i t i o n a l pyramidal c e l l s in a l a y e r and a confluence of polymorphic  cells.  The  actual presence  and  appearance of t h i s f i e l d  extremely v a r i a b l e across species (Geneser-Jensen, 2.5.3.2 F i e l d - GA^; and C A  3c  (Lorente de No,  those of CA ) 2  1934).  The  radiatum  This f i e l d 1934).  The  1972).  i s subdivided  pyramidal  into CA ,  CA ,  3g  c e l l s of CA^  3b  (along with  are the giant pyramids of the hippocampus (Lorente de a p i c a l dendrites  without  lateral  of the  CA^  pyramid  a r b o r i z a t i o n and  branches in stratum moleculare  is  penetrate  terminate  (Lorente de No, 1934).  with  the 2-3  No,  stratum vertical  Thick spines at the  proximal p o r t i o n of these dendrites r e c e i v e e x c i t a t o r y inputs from the mossy f i b e r s of FD  (Lorente  synapses at both  de  No,  1934).  the a p i c a l and  Subfield CA  basal  3 c  pyramids have  d e n d r i t e s , whereas C A  3 a  and  such CA-^  pyramids have only a p i c a l synapses with mossy f i b e r s (Lorente de No, 1934). The axon of the CA^ pyramid i s a t h i c k f i b e r that goes to the f i m b r i a , where i t gives o f f a number of c o l l a t e r a l s Lorente de No, 1934).  (Ramon y C a j a l ,  1893;  Most of these c o l l a t e r a l s are s h o r t , terminating i n  stratum o r i e n s or i n t e r p y r a m i d a l l y . discovered by S c h a f f e r i n 1892.  The most notable i s a t h i c k c o l l a t e r a l This c h a r a c t e r i s t i c Schaffer  collateral  penetrates the stratum pyramidale to run in the stratum radiatum and t e r m i nates near the j u n c t i o n of CA^ 1892).  a  and CA^  b  (Ramon y C a j a l , 1893;  The S c h a f f e r c o l l a t e r a l i s present i n n e a r l y a l l C A  3 c  Schaffer,  axons, about  50% of CA.,,3D and n e a r l y absent i n CA oa axons (Lorente de No, 1934). Q  2.5.3.3 F-i-el-d -CAg.c e l l s between CA^  and CA,  This i s a t r a n s i t i o n f i e l d of g i a n t (Lorente de No,  1934).  pyramidal  These c e l l s are  smal-  - 23 l e r than those of CA^ and lack both the d e n d r i t i c spines and the S c h a f f e r collaterals. very  thin  These pyramids stratum  are arranged i n i r r e g u l a r rows which form a  pyramidale.  Toward  subfield  CA^ , c  this  thin  layer  t h i c k e n s with the i n t r o d u c t i o n of more pyramidal c e l l s . 2.5.3.4 Field--GA^.  The  CA^  field  f i e l d s a, b, and c (Lorente de N6\ 1934).  i s a l s o d i v i d e d into  sub-  The border between the s u b f i e l d s  are not well d e f i n e d , but the r e s p e c t i v e pyramidal c e l l s are m o r p h o l o g i c a l l y different:  amongst the CA^  a  pyramids  are s u b i c u l a r c e l l s ; C A ^  have the  s m a l l e s t pyramidal c e l l s of a l l CA f i e l d s , and CA-^ pyramids are r e l a t i v e l y l a r g e (Lorente de No, 1934).  The a p i c a l d e n d r i t e s of CA-^ pyramids lack  s y n a p t i c spines at the proximal p o r t i o n of the primary s h a f t (Ramon y C a j a l , 1893).  In the stratum radiatum, these d e n d r i t e s a r b o r i z e e x t e n s i v e l y i n t o  very f i n e  branches,  where numerous f i n e  spines form  synapses  S c h a f f e r c o l l a t e r a l s (Lorente de No, 1934; Ramon y C a j a l , 1893).  with  the  Basal den-  d r i t e s form short t u f t s of i r r e g u l a r branches i n the stratum o r i e n s (Ramon y C a j a l , 1893). The  CA-^  primary  axon  is a thin  fiber  that e s s e n t i a l l y  through the stratum o r i e n s to the f i m b r i a (Lorente de No, 1934).  courses Axon c o l -  l a t e r a l s may cross the stratum pyramidale to ramify i n the stratum r a d i a tum.  Long r e c u r r e n t c o l l a t e r a l s a r i s e from some CA^ axons, t r a v e r s i n g the  stratum o r i e n s to run i n the alveus towards the f i m b r i a and the subiculum (Lorente de No, 1934).  At the border of CA^ and the subiculum, the dense-  l y packed stratum pyramidale a b r u p t l y stops; the pyramidal c e l l s d i s p e r s e and the stratum o r i e n s g r a d u a l l y t h i n s to a s i n g l e l a y e r i n the subiculum (Angevine, 1975; C h r o n i s t e r and White, 1975).  - 24 2.5.4 The  Neuronal-pathways-of orderly  lamination  the-hippocampus  of c e l l u l a r  i t an i d e a l model f o r s t u d y i n g c o r t i c a l  structure  i n t h e hippocampus make  organization.  The v a r i o u s s t r a t a o f  the hippocampus m a i n t a i n t h e i r r e l a t i v e o r i e n t a t i o n a l l a l o n g t h e l o n g i t u d i nal  axis.  In a d d i t i o n ,  organized i n p a r a l l e l axis  t h e major  1971)  with  This lamellar organization  the i n v i t r o  hippocampal  (Figure 2 ) . Although the t r i - s y n a p t i c  raises the p o s s i b i l i t y amplification  (Teyler  of fiber  slice  has been  (Skrede  system w i t h i n  and  and DiScenna, 1984), t h e r e appears  clearly  Westgaard,  t h e hippocampus  r e c r u i t m e n t and a cascade e f f e c t  d i v e r g e n c e from t h e l a m e l l a r o r g a n i z a t i o n (Andersen e t a l : ,  system i s  planes that are roughly transverse to the l o n g i t u d i n a l  (Andersen e t - a-1 -., 1971).  demonstrated  intrahippocampal t r i - s y n a p t i c  of signal  t o be v e r y  throughout t h e e n t i r e  little  hippocampus  1971).  2.5.5 A f f e r e n t s - t o - t h e - h i p p o c a m p u s 2.5.5.1 P e r f or ant -Path.excitatory 1893). rhinal  input  The p e r f o r a n t path (PP) c a r r i e s  t o t h e hippocampus  ( L o r e n t e de No, 1934; Ramon y  These f i b e r s o r i g i n a t e from t h e i p s i l a t e r a l cortices  (EC), c r o s s i n g  t h e major  t h e hippocampal  medial and l a t e r a l  fissure  the d e n d r i t e s o f t h e d e n t a t e g r a n u l e c e l l s , as w e l l  Cajal, ento-  t o form synapses a t  as w i t h t h e d e n d r i t e s o f  some CA3 pyramids ( H j o r t h - S i m o n s e n , 1973; Hjorth-Simonsen and Jeune, 1972). There  i s a topographical  specificity  t o t h e synapses  g i v e n p a r t o f t h e EC p r o j e c t o n l y t o a l i m i t e d sum,  but w i t h  (L#mo, 1971). the f i m b r i a  equal d e n s i t y  along the e n t i r e  Another main e x c i t a t o r y (Blackstad,  1956), which  i n that  i n p u t s from a  part o f the stratum granulolength  of the f a s c i a  dentata  i n p u t i s t h e commissural f i b e r s originate  from  the c o n t r a l a t e r a l  from CA,  Figure 2 Anatomical diagram o f a t r a n s v e r s e l y s e c t i o n e d r a t hippocampal s l i c e showing the various a f f e r e n t , e f f e r e n t and i n t r i n s i c pathways. Alv - alveus Comm - commissural input Ento - e n t o r h i n a l cortex Fim - f i m b r i a HF - hippocampal f i s s u r e mf - mossy f i b e r s pp - p e r f o r a n t path Sch - S c h a f f e r c o l l a t e r a l s  -  and al:,  CA4 pyramidal  cells  granule  A f f e r e n t s - to -the- - G A 3 - r e g i o n ;  dendrites  pyramidal CA , 3  (Blackstad  CA^.  synapses at the proximal  et--al:,  Their  primary  1978).  3c  granules  synapse only  (Lorente de No, 1934;  Swanson e t  The s y n a p t i c elements at the a p i c a l dendrites are noteworthy:  mossy f i b e r boutons, 3-6 urn i n diameter and length, completely branched  spines  evidence  o f mossy f i b e r synapses at the i n h i b i t o r y basket  (Frotscher,  The  o f the a p i c a l dendrite  which i s concrete  1985),  (Hamlyn,  evidence  commissural  projections  and terminate 1956;  from  ipsilateral  1966).  of CA  3  inhibition  1984).  o f the CA^  There i s some evidence field CA  4  1983).  A f f e r e n t s - -to - the- -GA^ -region;  T e y l e r and DiScenna,  dendrites  and c o n t r a l a t e r a l  The d i s t i n c t i o n o f f i e l d  i s not embraced by a l l workers (Blackstad, 1956;  Lorente  However, from Lorente de No  that mossy f i b e r s do not make giant synapses with spines,  cells  These f i b e r s run  1966).  on the basal  Andersen and L$mo,  the  and Sarvey,  2.5.5.3 2  i s also  input to CA^ o r i g i n a t e s i n the homotopic region o f  the f i m b r i a  (Schwerdtfeger  CA  There  1961).  1978).  pyramids (Blackstad, of  engulf the  f o r feedforward  the c o n t r a l a t e r a l hippocampus (Andersen and L0mo, through  shaft of  granule c e l l s synapse with a p i c a l dendrites o f the e n t i r e f i e l d  while the mossy f i b e r s from the infrapyramidal  (Douglas,  thin  Mossy f i b e r s from the supra-  1970).  with the basal dendrites o f s u b f i e l d C A al.,  Swanson e t  The axons of the dentate  c e l l s form the mossy f i b e r a f f e r e n t s to f i e l d  (0.2 pm) f i b e r s make en - passant 3  1977;  (Hjorth-Simonsen and Laurberg,  1978). 2.5.5.2  CA  26 -  s i n c e the l a t t e r are absent  from CA  ?  de No, 1934;  (1934),  i t i s clear  the a p i c a l d e n d r i t i c  pyramids.  Local  afferents  - 27 -  from  CA-^  (Lorente  axon  collaterals  de No, 1934);  make  synapses  commissural  at  projections  t h e CA2 b a s a l  dendrites  which  shown t o  t e r m i n a t e a t CA^ i n both s t r a t a r a d i a t u m and o r i e n s , have synapses  a t CA  2  by v i r t u e  have  been  can be i n t e r p r e t e d t o  o f t h e ambiguous d i s t i n c t i o n  between  these  two CA f i e l d s ( B l a c k s t a d , 1956). 2.5.5.4 A f f e r e n t s - t o t h e GA-^ - r e g i o n ; from  the i p s i l a t e r a l  stratum  radiatum  1934).  These  CA^  pyramids  (Andersen,  Schaffer  the f i n e l y arborized a p i c a l the  ipsilateral  g r e a t e s t response 1971).  CAg  Commissural  e-t- - a l ; ,  make numerous  input  or  the Schaffer  t h e CA-^ pyramids  projections  pyramids,  f o r m i n g en• p a s s a n t  (Andersen  et - a l ; ,  come  1980; B l a c k s t a d ,  i n the  1971; L o r e n t e  en•• passant  de No,  synapses  collaterals  the c o n t r a l a t e r a l  a t both  1956).  basal  elicits  CA^  and a p i c a l  The m a j o r i t y  with  Stimulation of  (Andersen, 1960; Andersen  from  synapses  t o CA^ i s  collaterals  d e n d r i t e s (Ramon y C a j a l , 1893).  pyramids  from  v i a the Schaffer  1960; Andersen  collaterals  The major  the  et- - a l ; , and CA^ dendrites  of these  synapses  are found a t t h e a p i c a l d e n d r i t e s i n t h e s t r a t u m r a d i a t u m . Lorente the  alveus  evidence  (1934)  activation  i n adjacent neither  collateral  described  t o t e r m i n a t e on  Consequently, potential  de No  collaterals  the basal  aspects  o f CA-^ pyramids CA-^  pyramids  supports  (Swanson e t - a l ; ,  2.5.6  E f f e r e n t s from  Aside  from  nor  ascend  o f t h e CA-^-CA  2  generates  (Andersen,  rules  o f CA^ t h a t  an  apparent  1975).  out t h e e x i s t e n c e  from  pyramids. synaptic  Autoradiographic of  this  short  1978). the-hippocampus  commissural  output  to the c o n t r a l a t e r a l  hippocampus,  o n l y major e f f e r e n t from t h e hippocampus i s from CA-^ pyramids  the  to the subi-  - 28 culum (Lorente de No, 1934; Swanson e t - a l : , 1978).  There i s anatomical e v i -  dence of a r e c u r r e n t c o l l a t e r a l system from some parts of CA^ and a l l of CAj and CA  2  t h a t terminates back i n the e n t o r h i n a l c o r t e x ( H j o r t h -  Simonsen, 1973; Lorente de No, 1934; Swanson et a l ; , 1978).  However, s o l i d  e l e c t r o p h y s i o l o g i c a l evidence f o r t h i s r e c u r r e n t network i s l a c k i n g . 2.5.7  Interneurons  There are a number of interneuron types i n the v a r i o u s s t r a t a of the hippocampus, the most p r e v a l e n t being the basket c e l l s (Lorente de No, Ramon y C a j a l , 1893).  1934;  These basket c e l l s are d i s t r i b u t e d w i t h i n the p r i n c i -  ple c e l l l a y e r s of both CA and FD, in c l o s e p r o x i m i t y to the p r i n c i p l e c e l l s (Andersen et- a l : , 1964;  Lorente de No, 1934).  An axon of a basket  cell  a r b o r i z e s e x t e n s i v e l y , making 200-500 synapses with primary c e l l s w i t h i n a dense plexus of f i b e r s (Andersen et- - a l : , 1964; Strub-le -et a l : , 1978). the FD, the axon t e r m i n a l s synapse  In  at the soma and d e n d r i t e s of granule  c e l l s ( S t r u b l e et- - a l : , 1978), while those at the CA pyramids  terminate at  the soma, proximal d e n d r i t e and i n i t i a l segment of the axon (Blackstad and Flood, 1963; Kosaka, 1980; Seress and Ribak, 1983). Electrophysiological  evidence suggested  that a recurrent inhibitory  system was present i n the CA f i e l d (Spencer and Kandel, 1961). al.  (1963, 1964)  l o c a t e d the s i t e of the i n h i b i t i o n  Andersen et  at t h e c o m a of the  pyramidal c e l l s and proposed a c i r c u i t of feedback i n h i b i t i o n through which adjacent p r i n c i p l e c e l l s i n h i b i t t h e i r neighbours v i a axon c o l l a t e r a l s to the basket c e l l s (Andersen et - a l ; , 1963, Immunoreactive  1964; Kandel and Spencer,  1961).  s t a i n i n g of interneuron t e r m i n a l s f o r glutamic a c i d decar-  boxylase (GAD) showed that these interneurons e l a b o r a t e y-aminobutyric a c i d  - 29 (GABA) (Ribak et - -a-1.-, 1978;  Seress and Ribak, 1983).  The p o s s i b i l i t y of  feedforward i n h i b i t i o n was suggested by the o b s e r v a t i o n of very low t h r e s hold interneurons in the FD (Buzsaki and E i d e l b e r g , 1981, 1982; Douglas et a l ; , 1983).  L a b e l l i n g (Loy, 1978) and degeneration s t u d i e s ( F r o t s c h e r and  Zimmer, 1983)  support d i r e c t commissural  the c o n t r a l a t e r a l ipsilateral  homotropic  i n n e r v a t i o n of basket c e l l s  primary c e l l s .  i n n e r v a t i o n of CAg  basket c e l l s  from  E l e c t r o m i c r o s c o p y a l s o show by mossy f i b e r s  of the  FD  ( F r o t s c h e r , 1985). 2.5.8 L o n g i t u d i n a l - a s s o c i a t i o n - p a t h w a y Lorente de No (1934) f i r s t observed axon c o l l a t e r a l s from CA pyramidal c e l l s t h a t run p a r a l l e l to the long a x i s of the hippocampus. t e r a l s a r i s e from CAg pyramids which  These  lack a S c h a f f e r c o l l a t e r a l  colla(Lorente  de No, 1934), forming a dense plexus on the a p i c a l s i d e of the pyramidal cells.  The  CA  CA^  2  and  finely C  branched  d e n d r i t e s p r o j e c t along the a x i s to  d e n d r i t e s , thereby  ates of the t r i - s y n a p t i c  system  linking into  the r e l a t i v e l y  a powerful  (Hjorth-Simonsen, 1973; Swanson e t a-T:, 1978).  CAg , g  isolated  lamin-  inter-lamellar  The p h y s i o l o g i c a l  pathway signifi-  cance of t h i s pathway has not been e x p l o r e d . 2.6  S h o r t - t e r m - p o t e n t i a t i o n i n the hippocampus Gloor  (1955) observed  s t i m u l a t i n g the amygdala.  marked PTP  i n the f e l i n e  hippocampus  Increased spike amplitude of the hippocampal  ponse p a r a l l e l e d the decrease i n l a t e n c y to spike g e n e r a t i o n .  after res-  In a d d i t i o n ,  a decrease i n e x c i t a t o r y t h r e s o l d and s e v e r a l phases of p o s t - t e t a n i c depression were d e s c r i b e d . D i r e c t t e t a n i c s t i m u l a t i o n of a f f e r e n t s to the hippocampal  pyramidal c e l l , presumably  through commissural  f i b e r s v i a the f i m -  - 30 b r i a , led to PTP of the population EPSP and population latency (Campbell and S u t i n , 1959). path r e s u l t e d in PTP of pyramidal  Tetanic  spike, and decreased  s t i m u l a t i o n of the  perforant  c e l l population EPSP and population  (Gloor et- a l : , 1964); these authors  a t t r i b u t e d the PTP  t r a n s m i t t e r r e l e a s e , a pre-synaptic  event.  spike  to an increase  in  More recent studies of STP  in  the hippocampus and f a s c i a dentata have revealed several components that are analogous (Creager  to  those  found  at  the  neuromuscular  facilitation  et- - a l : , 1980), augmentation (McNaughton, 1982), and  p o t e n t i a t i o n (Racine and Milgram, 1983). presynaptic al••, 1985;  junction:  locus and  i s due  physiological significance  transmitter  STP.  function,  Creager e t - - a l . perhaps  (Abraham et  (1980) suggested  some r o l e  others suggest a p o s s i b l e r o l e f o r STP in short-term Racine and Milgram, 1983).  release  However, there i s no general agreement on the  s i g n i f i c a n c e of in normal  These authors agree that STP has a  to elevated  McNaughton, 1982).  post-tetanic  in  no  epileptogenesis;  memory (Goddard,  1980;  The other point of concurrence i s that STP  long-term p o t e n t i a t i o n are d e c i d e d l y d i f f e r e n t processes; not l e a d , by graded increments or c r i t i c a l  that i s , STP  t h r e s o l d , to LTP  and does  (McNaughton,  1982; T e y l e r e t - a l . , 1982). 2.7  Associative-induction-of-potentiation:--afferent-cooperativity Long-term  substrate  potentiation  for learning  memory.  the  most  Several  promising  candidate  c h a r a c t e r i s t i c s of  as  a  LTP  are  q u a l i t a t i v e l y s i m i l a r to some s a l i e n t features of l e a r n i n g and memory.  For  instance, LTP  and  i s now  i s input s p e c i f i c , showing p o t e n t i a t i o n only at the pathways  that have been t e t a n i z e d (homosynaptic p o t e n t i a t i o n ) (Andersen e t - a l : , Lynch et a l ; , 1977), and only a b r i e f event (tetanus)  i s necessary  1977; for a  - 31 prolonged e f f e c t . Recently, LTP in the dentate  gyrus and the hippocampus have been i n -  duced v i a c o - a c t i v a t e d a f f e r e n t s (Barrionuevo Levy and Steward, 1979;  and  Brown, 1983;  McNaughton et- a l ; , 1978).  Lee,  1983;  Long-term p o t e n t i a t i o n  can be induced only i f a large number of a f f e r e n t f i b e r s to the t a r g e t c e l l s are t e t a n i z e d in synchrony, whereas STP can be produced by t e t a n i c s t i m u l a t i o n of only one (McNaughton, 1983).  Rather than t e t a n i c s t i m u l a t i o n of one  a f f e r e n t pathway, a s s o c i a t i v e i n d u c t i o n allows two or more separate but convergent pathways to  cooperate.  McNaughton et- a l ; , (1978) f i r s t a f f e r e n t s i n the f a s c i a dentata.  showed c o o p e r a t i v i t y of  They t e t a n i z e d  the  e n t o r h i n a l pathways e i t h e r s e p a r a t e l y or simultaneously  lateral  co-active and  medial  to produce LTP.  It  should be noted that these separate but convergent pathways are independentl y capable  of p o t e n t i a t i o n .  When the two  pathways were t e t a n i z e d  simul-  taneously, the r e s u l t a n t LTP was equal to and often greater than the sum the  independently  produced LTP.  Furthermore, these  spike discharge of the postsynaptic granule c e l l was for the i n d u c t i o n of LTP.  authors in i t s e l f  showed  that  insufficient  Their conclusion that LTP i s a cooperative pheno-  menon a l s o r e s t s on the f i n d i n g that stimulus i n t e n s i t y , and not tetanus quency or duration, i s the determinant f o r LTP; a c t i v a t e synchronously  of  more f i b e r s of d i f f e r i n g  high i n t e n s i t y tetanus thresholds  frecan  to produce a  l a r g e r LTP than a tetanus of lower i n t e n s i t y . This dependence of LTP magnitude on stimulus i n t e n s i t y has since been found by other workers (Lee, Wigstrom and Gustafsson,  1983a)  1983;  - 32 Another v a r i a t i o n of a s s o c i a t i v e i n d u c t i o n of LTP i n v o l v e s the p a i r i n g of a weak and a strong tetanus  (Barrionuevo  and Brown, 1983).  In t h i s s t u -  dy, both a weak input and a strong input were each located i n the a f f e r e n t fibers  of  pyramidal  the  stratum  cells.  radiatum  Stimulation  that  converge  of these  on  a  population  non-overlapping  t e t a n i c s t i m u l a t i o n of the strong  depression  CA^  pathways a f f e c t e d  d i f f e r e n t i a l l y the c o n t r o l response to a c o n t r o l stimulus put:  of  at the weak i n -  input r e s u l t e d i n  heterosynaptic  (Lynch e t a l : , 1977); t e t a n i c s t i m u l a t i o n of the weak input r e -  s u l t e d i n PTP.  However, when both pathways were stimulated  the weak c o n t r o l stimulus e x h i b i t e d PTP  and LTP.  Kelso and  simultaneously, Brown (1986)  have shown t h a t the two t e t a n i w i l l not induce a s s o c i a t i v e LTP i f separated by 200 msec.  Levy and Steward (1983) have described the temporal  ments f o r a s s o c i a t i v e LTP and  long-term  depression.  that LTP can be induced without temporal  These authors  showed  overlap, but the separation between  weak and strong inputs cannot exceed 5-20 msec, otherwise, sion masks any manifestations  require-  of LTP.  long-term  depres-  Douglas (1978) had reported  a  2-3  msec i n t e r v a l f o r a s i m i l a r induction of LTP. Thus, i t appears that a s s o c i a t i v e i n d u c t i o n of p o t e n t i a t i o n has ral c r i t e r i a :  1.  seve-  A c r i t i c a l t e t a n i c stimulus i n t e n s i t y must be exceeded,  the stimulus i n t e n s i t y being greater than the minimal needed to produce an EPSP (McNaughton et - a 1 ~., 1978);  2.  The a s s o c i a t i v e l y p o t e n t i a t e d pathway  does not have to produce LTP by i t s e l f (Barrionuevo  and Brown, 1983);  3.  The p a i r i n g or a s s o c i a t i o n of the separate a f f e r e n t s must take place w i t h i n a narrow temporal Steward, 1983);  window (Douglas, 4.  1978;  Kelso and  Brown, 1986;  Levy  and  Spike discharge of the p o s t s y n a p t i c c e l l i s not neces-  -  33 -  sary f o r a s s o c i a t i v e induction of LTP (Douglas, 1978; e t - a l ; , 1978;  Wigstrom e t - a l ; ,  Lee, 1983;  McNaughton  1983) 3 METHODS  3.1  Preparation of s i i c e s Male Wistar r a t s  dessicator j a r . gas c o n t a i n i n g the c o n t a i n e r .  (75-125  g) were placed on top of an i c e pack i n s i d e a  The d e s s i c a t o r j a r was 2% halothane in 95%  0 and 5% C0 2  2  anesthetic  (carbogen) was  The i c e pack lowered the body temperature to  sured r e c t a l l y ) , presumably decreasing 20-30  closed and a mixture of  fed  31-32°C  into (mea-  the body's metabolic demands.  After  minutes, the r a t was taken from the d e s s i c a t o r j a r and the top of the  s k u l l exposed v i a an a n t e r o p o s t e r i o r  i n c i s i o n of the s k i n .  The s k u l l p l a t e s  were c a r e f u l l y removed and the dura mater s l i t open to expose the b r a i n . A copious amount (about 10 mL)  of c o l d (4°C)  normal perfusate was poured onto  the brain to cool i t as well as to c l e a r the f i e l d of blood. separated  The brain  was  from the s p i n a l cord with a t h i n blade at the pontine l e v e l . The  o l f a c t o r y t r a c t s were then severed, followed nerves, and the whole brain was about 5 mL of c o l d medium was  by  severance of the  optic  then removed from the c r a n i a l v a u l t .  Again  poured over the brain before  one  or both  hippocampi were d i s s e c t e d f r e e . The f r e e d hippocampus was placed on the c u t t i n g platform with i t s long axis perpendicular  to the blade of the Mcllwain t i s s u e chopper.  campus was chopped i n t o transverse s l i c e s of 500  The hippo-  urn t h i c k and t r a n s f e r r e d as  - 34 a whole to a nylon net submerged with carbogen.  i n a p e t r i dish o f c o l d medium s a t u r a t e d  The s l i c e s were then c a r e f u l l y separated with a s p a t u l a and  about s i x s l i c e s were arranged on the nylon net; the remaining s l i c e s were discarded.  A second nylon mesh was  placed over the s l i c e s ,  anchoring them i n a sandwich arrangement. s l i c e s during the experiment.  effectively  This prevented movement of the  These sandwiched s l i c e s were taken from the  p e t r i d i s h and placed i n the s l i c e chamber, where they were perfused with normal medium at a r a t e of 3 ml/min.  Elapsed time between the s t a r t o f s u r -  gery and placement i n the s l i c e chamber d i d not exceed 3 minutes. While i n the s l i c e chamber, the s l i c e s were submerged  i n carbogen  s a t u r a t e d normal medium; about 0.5 mm of p e r f u s a t e covered the top s u r f a c e of the s l i c e s .  In a d d i t i o n , a constant stream of h u m i d i f i e d carbogen flowed  over the top of the medium.  A p i e c e of p a r a f i l m was placed over the chamber  opening f o r the d u r a t i o n of the one hour e q u i l i b r a t i o n period to maintain an oxygen-saturated atmosphere.  During e q u i l i b r a t i o n , the bath was  kept at  room temperature (24°C). A l l experiments were done at a bath temperature of 32 ± 0.2°C.  Flow r a t e of the medium remained unchanged.  To minimize v a r i a -  b i l i t y due to d i f f e r e n t d u r a t i o n s of ex - vivo p e r f u s i o n , o n l y one s l i c e from each animal was used per experiment.  Only those s l i c e s which e x h i b i t e d a  s t a b l e response to a t e s t stimulus (60-100 uA, 0.2 msec d u r a t i o n , negative pulses) over a 30 minute period were used. 3.2  Slice-bath The s l i c e bath has been d e s c r i b e d i n d e t a i l i n a p u b l i c a t i o n from t h i s  l a b o r a t o r y (Murali Mohan and S a s t r y , 1984). i l l u s t r a t i o n of the i n - v i t r o s l i c e bath.  F i g u r e 3 gives a diagrammatic  B a s i c a l l y , the bath has an alumi-  - 35  -  Fi gure 3 Diagrammatic i l l u s t r a t i o n o f the s l i c e bath used f o r e l e c t r o p h y s i o l o g i c a l recordings from i n v i t r o hippocampal s l i c e s .  - grounding pin GW - ground wire GP  HA - h u m i d i f i e d a i r HB - heater block IN - inner net LM - medium l i n e s LS - s u c t i o n l i n e MF - manifold ON - outer net SC - s l i c e chamber SS - s e c u r i n g screw TP  - temperature probe  TR  - temperature r e g u l a t o r  - 37 num heating block placed beneath the c i r c u l a r chamber where the s l i c e s were perfused.  A temperature  hippocampal  sensing device attached to the block  fed back to a r e g u l a t o r where the bath temperature was set and d i s p l a y e d .  A  length of polyethylene tubing was threaded through holes bored i n the aluminum b l o c k .  One end of t h i s tubing was i n s e r t e d through a hole d r i l l e d i n t o  the s i d e of the chamber; t h i s i s the i n l e t .  P e r f u s i n g medium fed i n t o the  other end of the tubing from a r e s e r v o i r was heated v i a the aluminum block to approximately bath temperature before e n t e r i n g the chamber.  Waste medium  flowed beyond the c i r c u l a r chamber i n t o a long trench where i t was a s p i r a t e d by gentle s u c t i o n . The p o s i t i o n of the s u c t i o n tube determined the depth of the p e r f u s a t e at the chamber.  Humidified carbogen was blown over the s l i c e s  through a tube f i x e d to the top of the bath and the whole bath was f i x e d to a s t a i n l e s s s t e e l p l a t e v i a two  screws.  The switching of perfusates was f a c i l i t a t e d by a manifold between the r e s e r v o i r ( s ) and the bath i n l e t tubing.  Changing  the p e r f u s i n g medium was  accomplished simply by clamping shut a l l but the d e s i r e d tubing to the manifold.  The normal and p i c r o t o x i n media were contained in d i f f e r e n t r e s e r -  v o i r s ; each medium was  independently saturated with carbogen  at the r e s e r -  voirs. 453  KC1, mM;  Perfusion-media The normal medium was  of the f o l l o w i n g composition:  3.1  mM;  mM;  NaH P0 , 1.3 2  dextrose 10 mM.  with carbogen. following  4  NaHC0  3>  26  mM;  CaCl , 2  NaCl, 120 2 mM;  mM;  MgCl , 2  2  The pH of t h i s medium was s t a b l e at 7.4 while aerated  The p i c r o t o x i n medium contained the same components with the  changes:  NaH P0,, ?  0  mM;  CaCl , ?  4  mM;  MgCl  ?  4  mM;  picro  - 38 toxin 0.01 mM. It has been reported that the GABA^ antagonist, p i c r o t o x i n , can f r e e the i n - v i t r o hippocampal s l i c e of GABAergic i n h i b i t i o n , thereby the i n d u c t i o n of LTP (Wigstrom and Gustafsson, p i c r o t o x i n also induces  facilitating  1983b, 1985a).  However,  e p i l e p t i f o r m a c t i v i t y i n the hippocampus ( H a b l i t z ,  1984) which n e c e s s i t a t e d the increase of both d i v a l e n t c a t i o n s i n the perf u s i n g medium:  calcium and magnesium were elevated to s t a b i l i z e the c e l l u -  l a r membrane.  The higher CaCl,, concentration  led to s o l u b i l i t y  difficul-  t i e s that were remedied by the omission  of NaH2P0^.  Notwithstanding  the  omission, the p i c r o t o x i n medium maintained  i t s b u f f e r i n g c a p a c i t y , showing a  steady pH of 7.4 while aerated with carbogen. 3.4  Stimulation-systems In most experiments, the e x t r a c e l l u l a r s t i m u l a t i o n e l e c t r o d e s  were m e t a l l i c (SNEX 100, Rhodes E l e c t r o n i c s , r e s i s t a n c e 1-2 Mfi).  The con-  c e n t r i c c o n f i g u r a t i o n of these b i p o l a r e l e c t r o d e s minimized current beyond the stimulus  site.  Current  Grass Instruments S88 s t i m u l a t o r . through  pulses were generated Pulses  by a 2  from each channel  a Grass Instruments PSIU6 constant current stimulus  before reaching  their respective stimulating electrodes.  used  spread channel  were  passed  isolation unit A l l stimulation  pulses were negative square waves. For i n t r a c e l l u l a r d e p o l a r i z a t i o n , a monopolar glass e l e c t r o d e  filled  with 1 M KC1 and 1.6 M K c i t r a t e served the dual purpose o f s t i m u l a t i n g and recording (see f o l l o w i n g s e c t i o n ) .  A 4 M N a C l - f i l l e d glass  or  electrode  a fine-tip  monopolar  tungsten  was  used  microelectrode  to s t i m u l a t e  Schaffer c o l l a t e r a l terminal regions i n e x c i t a b i l i t y t e s t i n g .  the  - 39 3.5  Recording-systems Recording  tubing  microelectrodes  were  pulled  ( b o r o s i l i c a t e g l a s s , O.D. 1.5 mm,  Co.) using  a Narishige  from  fibre-filled  I.D. 1.0 mm,  PE-2 microelectrode  puller.  Frederick  capillary Haer and  E x t r a c e l l u l a r micro-  e l e c t r o d e s were f i l l e d with 4 M NaCl and had t i p s of approximately 1 urn. Typical  resistance  was 1-2 Mfi.  E x t r a c e l l u l a r s i g n a l s were a m p l i f i e d  e i t h e r a World P r e c i s i o n Instruments DAM-5A d i f f e r e n t i a l p r e a m p l i f i e r Medical  Systems Neurolog AC-preamplifier  s i g n a l s were then d i s p l a y e d  and AC-DC a m p l i f i e r .  by or a  The a m p l i f i e d  on a Data P r e c i s i o n DATA 6000 waveform ana-  lyzer.  Evoked responses were stored and averaged by the analyzer  copies  of the averaged records  and hard  (4-8 sweeps) were p l o t t e d on paper by a  Hewlett-Packard 7470A graphics p l o t t e r . I n t r a c e l l u l a r recording/current  i n j e c t i o n e l e c t r o d e s were a l s o p u l l e d  from the same c a p i l l a r y tubing with the Narishige  puller.  Electrode  tips  were sub-micron i n s i z e and were f i l l e d with 1 M KC1 and 1.6 M K c i t r a t e . Typical  resistances  were 40-50 Mfi. Signals  were a m p l i f i e d  P r e c i s i o n Instruments (WPI) M-707 i n t r a c e l l u l a r a m p l i f i e r .  with a World Current  pulses  generated by the Grass Instruments S88 s t i m u l a t o r were d i r e c t e d to the current i n j e c t i o n c i r c u i t b u i l t into the WPI M-707 a m p l i f i e r . and  i n t r a c e l l u l a r responses were monitored on a Tektronix  beam storage o s c i l l o s c o p e .  pulses  type 5113 dual  Records were e i t h e r captured on p o l a r o i d f i l m or  p l o t t e d using the Hewlett-Packard 7470A graphics ments, the a m p l i f i e d  Current  p l o t t e r ( i n some e x p e r i -  responses were fed to the DATA 6000 u n i t where 4-8  sweeps were averaged and p l o t t e d ) .  - 40 3.6  A s s o c i a t i v e - induction of STP 3.6.1 C o n d i t i o n i n g - b y - t e t a n i c s t i m u l a t i o n - o f f i b e r s These experiments were done i n p i c r o t o x i n - c o n t a i n i n g medium.  The e f -  f e c t s o f t e t a n i c c o n d i t i o n i n g t r a i n s on the i n d u c t i o n o f STP were examined. A b i p o l a r t e s t s t i m u l a t i n g e l e c t r o d e (S2) was placed i n the stratum r a d i a tum o f the CA3 region to s t i m u l a t e the S c h a f f e r c o l l a t e r a l s 5).  (Figures 4,  The s t i m u l a t i n g current o f the t e s t input ( S ) was adjusted 2  to pro-  duce a "weak" (200-600 yV) population EPSP as recorded i n the a p i c a l d e n d r i t i c area o f CA^.  The c o n d i t i o n i n g e l e c t r o d e was placed  possible positions:  i n the stratum  radiatum  i n one o f three  on the s u b i c u l a r side o f the  r e c o r d i n g e l e c t r o d e (Figure 4 ) ; i n the stratum o r i e n s (Figure 4 ) ; and i n the alveus  (Figure 5) to s t i m u l a t e  the CA-^ pyramidal  cells  antidromically.  This c o n d i t i o n i n g input was the "strong" input (S^) which produced t i v e l y l a r g e responses  at the r e c o r d i n g s i t e :  rela-  stratum radiatum EPSP was 1-3  mV; stratum o r i e n s EPSP was 2-5 mV, with a superimposed population spike o f 0.5-1 mV; and the a l v e a r antidromic compound a c t i o n p o t e n t i a l was 3-7 mV. The recording e l e c t r o d e was placed i n the a p i c a l d e n d r i t i c region o f CA^ where a t e s t impulse 5).  from S  2  produced the maximal EPSP (Figures  The s t i m u l a t i n g e l e c t r o d e s f o r a c t i v a t i n g the S-^ and S  placed so that non-overlapping  a f f e r e n t s would be s t i m u l a t e d .  was t e s t e d by paired pulse experiments. pulse  stimulation  t i a t e d over  I f the "strong"  inputs were  2  This c r i t e r i o n  The second t e s t response to paired  ( i n t e r s t i m u l u s i n t e r v a l o f 50 msec) of S  control.  4,  input  2  was  poten-  (S^) was a c t i v a t e d 50 msec  before a s i n g l e pulse of S , then the t e s t response showed e i t h e r no change 2  or a s l i g h t decrease  i n amplitude  (heterosynaptic depression [Lynch  et-al;,  Figure 4 Experimental arrangement f o r a s s o c i a t i v e induction of STP by c o n d i t i o n i n g of stratum radiatum and stratum o r i e n s . C o n d i t i o n i n g t r a i n s c o n s i s t e d o f 10 pulses a t 100 Hz (1-10 t r a i n s at 5 second i n t e r v a l s ) and were e i t h e r d e l i vered alone or in conjunction with a s i n g l e stimulus of the t e s t (S2) input at 1 msec f o l l o w i n g the i n i t i a t i o n of each t r a i n . In some e x p e r i ments, the temporal r e l a t i o n s h i p between the c o n d i t i o n i n g t r a i n and the t e s t EPSP f o r STP i n d u c t i o n was determined. The t e s t s t i m u l a t i o n (S2) was given at various i n t e r v a l s between -100 and +100 msec with r e s p e c t to the onset of the c o n d i t i o n i n g t r a i n ( S i , stratum o r i e n s ) . R - e x t r a c e l l u l a r recording electrode Sio - s t i m u l a t i n g e l e c t r o d e f o r stratum o r i e n s c o n d i t i o n i n g S\ - s t i m u l a t i n g e l e c t r o d e f o r stratum radiatum c o n d i t i o n i n g S2 - s t i m u l a t i n g e l e c t r o d e f o r evoking stratum radiatum t e s t population EPSP 0  r  Figure 5 Experimental arrangement f o r a s s o c i a t i v e induction o f STP by alvear c o n d i t i o n i n g . As i n the case o f stratum radiatum and stratum o r i e n s c o n d i t i o n ing, alvear c o n d i t i o n i n g a l s o c o n s i s t e d o f t r a i n s o f 10 pulses a t 100 Hz (1-10 t r a i n s given every 5 seconds). These c o n d i t i o n i n g t r a i n s were e i t h e r d e l i v e r e d alone or p a i r e d with a s i n g l e stimulus o f the stratum radiatum t e s t input (S2) a t 1 msec f o l l o w i n g t h e onset o f the t r a i n . R - e x t r a c e l l u l a r recording electrode 51 - s t i m u l a t i n g e l e c t r o d e f o r a l v e a r c o n d i t i o n i n g 52 - s t i m u l a t i n g e l e c t r o d e f o r evoking t e s t stratum radiatum population EPSP  - 43  This  1977]).  indicates  no overlap  f e r e n t s r e s u l t e d i n a potentiated experiments (see Figure 8A_).  mized.  between S S  and  2  response with  2  Only non-overlapping  overlapping  S-^;  the S  paired  2  afpulse  inputs were used i n the  Since a l l experiments were done i n 10 pM p i c r o t o x i n , the pos-  experiments. sibility  -  of an i n h i b i t i o n masking a potentiated The frequency  of S^ and S  2  S  2  response was  s t i m u l a t i o n s was 0.1  mini-  Hz so that each  stimulus a l t e r n a t e d at 5 second i n t e r v a l s . The impulses.  conditioning  tetanus  was  delivered  t r a i n every 5 seconds).  s t i m u l a t i o n of S  2  One, f i v e or ten Hz (one  Each t r a i n was e i t h e r d e l i v e r e d alone (without the S ) or p a i r e d  S^ and S  2  with  2  at 1 msec a f t e r the onset  tetanic conditioning,  frequency of 0.1  as t r a i n s of  of m u l t i t r a i n c o n d i t i o n i n g was 0.2  concomitant a c t i v a t i o n of the t e s t input,  3.6.2  S^  Each t r a i n c o n s i s t e d of 10 impulses at 100 Hz.  t r a i n s were given; the frequency  After  through  a single  of the c o n d i t i o n i n g t r a i n .  were returned  to the  pre-tetanus  Hz.  Gonditioning b y - i n t r a c e l l u l a r d e p o l a r i z i n g - pulses  The r o l e of postsynaptic c e l l d e p o l a r i z a t i o n i n the a s s o c i a t i v e  induc-  t i o n of STP and LTP was examined using i n t r a c e l l u l a r recording (see Figure 6 for  experimental  arrangement).  Two separate  t e s t inputs  one i n stratum o r i e n s and one i n stratum radiatum. ing  electrode  c e l l EPSPs.  at the stratum Stimulus  were used here:  An i n t r a c e l l u l a r r e c o r d -  pyramidale o f the CA-^ area  recorded  single  i n t e n s i t y f o r each t e s t input was adjusted to produce  a "weak" EPSP of about 30% of maximum.  Control  s t i m u l a t i o n frequency f o r  each input was once every 15 seconds; they were a l t e r n a t e d so t h a t there was an i n t e r v a l of 7.5 seconds between each successive  stimulation.  - 44 R / D  Experimental arrangement f o r a s s o c i a t i v e i n d u c t i o n of STP by i n t r a c e l l u l a r i n j e c t i o n o f d e p o l a r i z i n g c u r r e n t . I n t r a c e l l u l a r d e p o l a r i z i n g pulses (3-10 nA, 75-200 msec duration) were e i t h e r given alone or p a i r e d with a s i n g l e s t i m u l a t i o n of the stratum radiatum t e s t EPSP (S2) a t 1 msec f o l l o w i n g onset o f the pulse. The stratum oriens t e s t EPSP ( S i ) served as a c o n t r o l and was not paired with any d e p o l a r i z i n g i n j e c t i o n s . R/D - i n t r a c e l l u l a r e l e c t r o d e f o r r e c o r d i n g and i n j e c t i o n o f d e p o l a r i z i n g current pulses 51 - s t i m u l a t i n g e l e c t r o d e f o r evoking t e s t stratum o r i e n s EPSP 52 - s t i m u l a t i n g e l e c t r o d e f o r evoking t e s t s t r a t u m r a d i a t u m EPSP  - 45 Instead  of a separate  suprathreshold through the  input  f o r the  conditioning  tetanus  trains,  d e p o l a r i z i n g pulses were i n j e c t e d i n t o the impaled CA-^ intracellular electrode.  duration; 3-10  These d e p o l a r i z a t i o n s  cell  (75-200 msec  nA; one, f i v e or ten d e p o l a r i z i n g commands at 0.2  Hz) were  used to mimic the e f f e c t s of s y n a p t i c a l l y d r i v e n d e p o l a r i z a t i o n s induced t e t a n i of inputs.  The  d e p o l a r i z a t i o n s were given  e i t h e r alone or  by  paired  with one s t i m u l a t i o n of the stratum radiatum t e s t input at 1 msec a f t e r the onset of the d e p o l a r i z a t i o n .  The stratum o r i e n s input was never paired with  any d e p o l a r i z i n g current i n j e c t i o n s , thus serving as a secondary c o n t r o l in the experiment. 3.6.3 The  Temporal-requirements-governing-the-induction  of STP  temporal r e l a t i o n s h i p between the c o n d i t i o n i n g  t e s t stimulus  was  examined by varying  the  tetanus  2  evoked by s t i m u l a t i o n of stratum  input (S^) was input was  oriens  of  The t e s t input  radiatum while the  evoked by s t i m u l a t i o n of stratum  stimulated at 0.1  the  i n t e r v a l between the onset  t e t a n i c s t i m u l a t i o n and the s t i m u l a t i o n of the t e s t input. (S ) was  and  conditioning  (Figure 4 ) .  Each  Hz ( a l t e r n a t i n g every 5 seconds) except during  the c o n d i t i o n i n g tetanus, which was t r a i n c o n s i s t i n g of 10 pulses  f i x e d at f i v e t r a i n s at 0.2  at 100  Hz.  The  t e s t stimulus  Hz,  (S ) 2  each either  preceded or succeeded the onset of each t e t a n i c c o n d i t i o n i n g t r a i n by i n t e r v a l of 0-100 3.7  an  msec.  A s s o c i a t i v e - •induction  of- - -Schaffer- - c o l l a t e r a l - terminal - - e x c i t a b i l i t y  changes Changes in presynaptic method of Wall  (1958).  terminal  Figure  e x c i t a b i l i t y were assessed  7 shows the  experimental  using  arrangement.  the A  - 46 -  Figure 7 Experimental arrangement f o r e x c i t a b i l i t y t e s t i n g o f Schaffer c o l l a t e r a l terminal r e g i o n s . The e x t r a c e l l u l a r r e c o r d i n g e l e c t r o d e (R) was placed i n the CA3 c e l l body l a y e r to monitor a l l - o r - n o n e a c t i o n p o t e n t i a l s i n s i n g l e CA3 neurons. The CA3 neuron recorded from was a c t i v a t e d by s t i m u l a t i o n at the Schaffer c o l l a t e r a l terminal regions (S2) l o c a t e d a t the a p i c a l d e n d r i t i c region of C A i . The e x c i t a b i l i t y o f the terminal regions ( d e t e r mined by the amount o f current r e q u i r e d to discharge the c e l l i n 1-2 o f 3 consecutive attempts) was monitored before and a f t e r c o n d i t i o n i n g . Condit i o n i n g t r a i n s . were d e l i v e r e d e i t h e r to stratum o r i e n s ( S i ) o r stratum radiatum ( S i ) arid c o n s i s t e d o f 1, 5 o r 10 t r a i n s o f 10 pulses a t 100 Hz given every f i v e seconds. The c o n d i t i o n i n g was e i t h e r given alone or p a i r e d with a s i n g l e suprathreshold stimulus o f the t e s t f i b r e a t 1 msec f o l l o w i n g the onset o f each t r a i n . It was confirmed t h a t the c o n d i t i o n i n g t r a i n s d i d not a c t i v a t e the experimental c e l l . 0  r  - 47 -  monopolar glass microelectrode  ( S ) or a f i n e - t i p monopolar tungsten 2  trode was p o s i t i o n e d i n the stratum  radiatum  o f f i e l d CA-^, presumably i n  the area of S c h a f f e r c o l l a t e r a l synapses at the a p i c a l d e n d r i t e s . t i o n o f the S c h a f f e r c o l l a t e r a l terminals through in  antidromic  soma.  all-or-none  action  An e x t r a c e l l u l a r recording  pyramidale "strong"  recorded  potentials electrode  these a c t i o n p o t e n t i a l s .  input (S^) was p o s i t i o n e d i n stratum  alone  recorded  d i d not induce  from i n f i e l d  CA . 3  an antidromic Tetanic  the S  2  Stimula-  electrode results  (AP) i n the CA3 placed  pyramidal  i n the CA3  stratum  An e l e c t r o d e t o a c t i v a t e a  in order to provide the c o n d i t i o n i n g tetanus. input  elec-  o r i e n s or stratum  radiatum  S t i m u l a t i o n of the "strong"  action potential  stimulations  i n the c e l l  o f S-^ (10 pulses  at  100 Hz; one, f i v e or ten t r a i n s ; one t r a i n every f i v e seconds) were d e l i vered  alone or paired with a s i n g l e s t i m u l a t i o n of S  stimulus  i n t e n s i t y was used) at 1 msec a f t e r the onset  Schaffer c o l l a t e r a l  terminal  current r e q u i r e d t o generate 2 o f 3 consecutive trode.  2  (a  suprathreshold  of the tetanus.  e x c i t a b i l i t y was measured as the amount o f an a c t i o n p o t e n t i a l i n the CA^ neuron i n 1 or  attempts by s t i m u l a t i o n through  the t e s t ( S ) e l e c -  An increase i n e x c i t a b i l i t y would be r e f l e c t e d as a decrease  amount o f c u r r e n t r e q u i r e d t o discharge the c e l l and v i c e versa. l e v e l o f current to produce the antidromic through  2  i n the  A baseline  a c t i o n p o t e n t i a l by s t i m u l a t i o n  the t e s t ( S ) e l e c t r o d e was determined once every 2 to 3 minutes 2  over 15 minutes before any c o n d i t i o n i n g s t i m u l a t i o n s were given. tempts were made f o r every stimulus i n t e n s i t y t e s t e d .  Three a t -  - 48 4 RESULTS 4.1  Stratum-radiatum-conditioning The e f f e c t s of strong c o n d i t i o n i n g t e t a n i on a weak population  ponse were examined  i n these  experiments.  Tetanic  stimulation  res-  of the  "strong" c o n d i t i o n i n g input (S^) without any concomitant a c t i v a t i o n o f the "weak" t e s t input ( S ) was i n s u f f i c i e n t i n i t s e l f to induce any p o t e n t i a 2  tion  o f the t e s t input  ( S ) . A l l unpaired 2  tetanic conditioning  trains  produced a degree o f depression  i n the t e s t response (85 ± 4% SEM o f c o n t r o l  at 60 seconds post-10 unpaired  t e t a n i c t r a i n s o f stratum  radiatum, 7 o f 8  expts., no change i n 1 of 8) (Figure 8A). P o t e n t i a t i o n of t h i s EPSP was induced  population  i f the c o n d i t i o n i n g tetanus was p a i r e d with one s t i m u l a t i o n  of the "weak" t e s t input at 1 msec a f t e r the onset o f each t r a i n . paired t r a i n , there was a b r i e f , small l a s t i n g about two minutes.  A f t e r one  p o t e n t i a t i o n of the t e s t response  Increasing the number o f paired t r a i n s to f i v e  markedly increased the s i z e o f the STP induced  (Figure 8A_). Repeated p a i r -  ings o f 1-5 t r a i n s l e d t o repeated STP with no apparent changes i n the durat i o n o f the p o t e n t i a t i o n ; depression ings.  d i d not s e t i n a f t e r repeated  pair-  The STP, measured at 60 seconds post-10 p a i r e d t r a i n s , was 184 ± 8%  SEM o f c o n t r o l and l a s t e d 2-3 minutes (6 o f 8 expts., no change i n 2 of 8 ) . This STP was followed by LTP (162 ± 5% SEM o f c o n t r o l at 15 minutes post-10 paired t r a i n s , 6 o f 8 expts., no change i n 2 o f 8 ) . Note t h a t  depression  due to unpaired t r a i n s d i d not increase p r o p o r t i o n a t e l y with the STP.  - 49  -  Figure 8 A s s o c i a t i v e induction o f STP, LTP and the reduction i n the Schaffer c o l l a t e r a l terminal e x c i t a b i l i t y . (A) The schematic diagram on the l e f t i l l u s t r a t e s the experimental arrangement. A b i p o l a r t e s t s t i m u l a t i n g e l e c t r o d e (S2) was p o s i t i o n e d i n the stratum radiatum and a b i p o l a r c o n d i t i o n i n g s t i m u l a t i n g e l e c t r o d e ( S i ) was p o s i t i o n e d i n another area o f the stratum radiatum. A r e c o r d i n g microelectrode ( c o n t a i n i n g 4 M NaCl) was p o s i t i o n e d in the a p i c a l d e n d r i t i c area o f CAi neurones t o monitor the t e s t EPSP evoked at 0.2 Hz ( s t i m u l a t i o n strength was adjusted t o obtain a response between 300-600 y V ) . The c o n d i t i o n i n g s t i m u l a t i o n strength was adjusted t o evoke a population EPSP o f 1-3 mV i n s i z e . I f a twin s t i m u l a t i o n of S? (50 ms i n t e r v a l ) r e s u l t e d i n a f a c i l i t a t i o n o f the second population EPSP (see i n s e t , l e f t ) and i f a s t i m u l a t i o n o f S i preceding S2 s t i m u l a t i o n by 50 ms r e s u l t e d i n no f a c i l i t a t i o n o f the second population EPSP (see i n s e t , r i g h t ) , then the S i and S2 s t i m u l a t i o n s were presumed t o a c t i v a t e separ a t e input f i b r e s . In a l l experiments, t h e e f f e c t o f unpaired c o n d i t i o n i n g t r a i n s (UC; i . e . , the t e s t s t i m u l a t i o n was o f f during the c o n d i t i o n i n g ; each c o n d i t i o n i n g t r a i n contained 10 pulses at 100 Hz) and o f p a i r e d c o n d i t i o n i n g t r a i n s (PC; i . e . , the t e s t s t i m u l a t i o n was on 1 ms a f t e r the onset o f each t r a i n ) were examined on the t e s t population EPSP. During the f i r s t 3 minutes a f t e r UC or PC, the response was monitored every 15 seconds and a t a l l other times a t 30 second i n t e r v a l s . The graph on the r i g h t shows r e s u l t s from one experiment. Note STP a f t e r 1 and 5 PCs, and LTP a f t e r 10 PCs. (B) E f f e c t s o f the c o n d i t i o n i n g on the e x c i t a b i l i t y o f the terminal region o f a S c h a f f e r c o l l a t e r a l . A monopolar t e s t s t i m u l a t i n g e l e c t r o d e (S2) was p o s i t i o n e d i n the a p i c a l d e n d r i t i c area of the CAi neurones t o a c t i v a t e (0.2 ms negative pulses, 3-10 yA, 0.2 Hz) the terminal regions o f Schaffer c o l l a t e r a l s so t h a t antidromic a l l - o r - n o n e a c t i o n p o t e n t i a l s (see i n s e t ) could be recorded from the CA3 c e l l bodies. A c o n d i t i o n i n g stimul a t i o n e l e c t r o d e ( S j ) was p o s i t i o n e d i n the stratum radiatum and t h e unpaired (UC) and p a i r e d (PC) c o n d i t i o n i n g t r a i n s were a p p l i e d as d e s c r i b e d in Au I t was confirmed t h a t the c o n d i t i o n i n g s t i m u l a t i o n d i d not a c t i v a t e the t e s t S c h a f f e r c o l l a t e r a l . During the PC, the s t i m u l a t i o n s t r e n g t h t o a n t i d r o m i c a l l y a c t i v a t e the t e s t S c h a f f e r c o l l a t e r a l was increased t o 2 times c o n t r o l to make sure that the f i b r e was a c t i v a t e d during PC. A s i m i l a r a c t i v a t i o n o f the t e s t f i b r e without the presence o f the c o n d i t i o n i n g produced no changes i n the e x c i t a b i l i t y o f the t e s t f i b r e ( r e s u l t s not shown). The amount o f c u r r e n t r e q u i r e d to produce an a l l - o r - n o n e a c t i o n p o t e n t i a l was taken as that which induced a spike i n 1-2 o f 3 c o n s e c u t i v e attempts. In the graph t o the r i g h t o f the schematic diagram, r e c o r d i n g s taken at 30 second i n t e r v a l s were p l o t t e d . Note that 1 and 5 PCs induced a 3 minute decrease while 10 PCs induced a prolonged decrease i n the e x c i t a b i l i t y o f the t e s t f i b r e t e r m i n a l . Results i n (A) and (B_) were from d i f f e r e n t experiments.  - 51 4.2  Stratumoriens-conditioning The e f f e c t s of stratum oriens c o n d i t i o n i n g on the t e s t stratum  tum  EPSP were q u i t e s i m i l a r to those seen above.  t r a i n s to the stratum  Unpaired  conditioning  o r i e n s input (5 t r a i n s of 10 pulses at 100  t r a i n every 5 seconds) led to depression  radia-  Hz,  one  of the t e s t EPSP (94 ± 2% SEM  c o n t r o l at 60 seconds post-5 unpaired t r a i n s , n = 23; see Figure 10). ing the c o n d i t i o n i n g tetanus with one stratum  of  Pair-  radiatum s t i m u l a t i o n at 1 ms  f o l l o w i n g the onset of each t r a i n led to STP (population EPSP as a % of control  at 60 seconds post-5 paired t r a i n s :  121  ± 4 SEM,  5 of 5  expts.).  Since the p h y s i c a l separation between the c o n d i t i o n i n g and t e s t inputs did not appear to a f f e c t the a s s o c i a t i v e i n d u c t i o n of p o t e n t i a t i o n , i t i s p o s s i ble to exclude  presynaptic  terminal  i n t e r a c t i o n s as necessary  criteria  for  The r o l e of the postsynaptic c e l l in a s s o c i a t i v e induction of STP  and  associative induction. 4.3  LTP  A1vear - c o n d i t i o n i n g  i s unclear.  cells,  i t was  discharge stimulated  Using  alvear s t i m u l a t i o n  CA^  p o s s i b l e to d e p o l a r i z e the CA-^ c e l l through a c t i o n p o t e n t i a l  that did not involve t r a n s s y n a p t i c with antidromic  conditioning  tetani  The CA-^ c e l l  induced  antidromic  was  unpaired  As with the above experiments, only the potentiation;  t r a i n s produced both STP and LTP (Table 1). t e t a n i , however, unpaired  responses.  t e t a n i c t r a i n s in the same paired and  manner as the previous experiments. paired  to a n t i d r o m i c a l l y a c t i v a t e  10  paired  conditioning  Unlike the s y n a p t i c a l l y driven  t e t a n i did not produce any s i g n i f i c a n t  depression of the t e s t response (98 ± 3 % SEM of c o n t r o l at 60 seconds post-10 paired t r a i n s , 6 of 6 e x p t s . ) .  - 52 -  Table l . P o s t - C o n d i t i o n i n g P o t e n t i a t i o n Induced by P a i r i n g T e t a n i c T r a i n s of the Alveus with a S i n g l e S t i m u l a t i o n of the Test .  Input.  Alveus  Time post-10 paired conditioning trains Test p o p u l a t i o n  EPSP  as a % o f c o n t r o l  60 s 146 ± 7 SEM n =6  15 min 133 ± 5 SEM n =4  - 53 4.4  I i n t r a c e l l u l a r current - i n j e c t i o n s Postsynaptic c e l l d e p o l a r i z a t i o n was f u r t h e r examined with  intracellu-  l a r c u r r e n t i n j e c t i o n s . A l l stratum o r i e n s e x t r a c e l l u l a r responses from the unpaired  stimulations  (Table 2). ing  exhibited  only  depression  a f t e r current  In the case of the stratum radiatum responses, the EPSPs f o l l o w -  p a i r i n g showed p o t e n t i a t i o n whereas the unpaired  (Table 2 ) .  EPSPs were depressed  This pattern of p o t e n t i a t i o n was s i m i l a r to t h a t of other e x p e r i -  ments i n v o l v i n g t e t a n i c c o n d i t i o n i n g t r a i n s :  i n c r e a s i n g the number of paired  d e p o l a r i z i n g commands r e s u l t e d in p r o g r e s s i v e l y l a r g e r STP. conditioning  injection  commands, STP  was  superimposed on LTP  With ten paired  (Figure 9, Table  This evidence c l e a r l y suggests the involvement of the postsynaptic  2).  c e l l in  associative induction. 4.5  Schaffer c o l l a t e r a l -terminal-excitability-changes Because STP  has been shown to be a presynaptic  phenomenon in  e x c i t a b l e j u n c t i o n s ( E c c l e s and K r n j e v i c 1959a, 1959b; Magleby and  other Zengel,  1975a, 1975b), i t i s p e r t i n e n t to the argument to examine concomitant pres y n a p t i c changes during a s s o c i a t i v e l y - i n d u c e d p o t e n t i a t i o n . i c c o n d i t i o n i n g t r a i n s to stratum  Unpaired t e t a n -  radiatum did not change the e x c i t a b i l i t y  of the S c h a f f e r c o l l a t e r a l terminals (amount of c u r r e n t to f i r e c e l l as a % of c o n t r o l :  98 ± 3 SEM at 60 seconds post-5 unpaired t r a i n s , 7 of 7 expts.;  99 ± 2 SEM at 60 seconds post-10 unpaired t r a i n s , 7 of 7 e x p t s . ) . l y , unpaired  t e t a n i to stratum  oriens a l s o r e s u l t e d in no a l t e r a t i o n s in  terminal e x c i t a b i l i t y (amount of current to discharge trol:  99 ± 3 SEM  Similar-  at 60 seconds post-5 unpaired  c e l l as a % of con-  t r a i n s , 6 of 6  expts.).  However, as can be seen in Figure 8, paired t e t a n i c c o n d i t i o n i n g led to a  -  54  -  Table 2. E f f e c t s of i n t r a c e l l u l a r l y i n j e c t e d d e p o l a r i z i n g current pulses on EPSPs evoked by s t i m u l a t i o n o f stratum radiatum and stratum o r i e n s . A.  Stratum radiatum t e s t EPSP Number o f c o n d i t i o n i n g pulses 5  1 UP  10  P  UP  P  UP  P  1 min postconditioning (EPSP as % of c o n t r o l )  Range Mean±SEM n  89 1  129-140 135 * 6 2  72-89 82 ± 3 5  96-186 134 ± 10 9  71-78 74 ± 1 4  95-218 145 ± 14 9  15 min postconditioning (EPSP as % of c o n t r o l )  Range Mean±SEM n  102 1  90-112 98 ± 5 2  91-113 100 * 6 5  89-109 103 ± 4 9  87-112 97 ± 5 4  99-162 122 ± 8 9  B . Stratum o r i e n s t e s t EPSP Number o f c o n d i t i o n i n g  1 min postconditioning (EPSP as % of c o n t r o l )  Range Mean±SEM n  15 min postconditioning (EPSP as % of c o n t r o l )  Range Mean±SEM n  pulses  1  5  10  UP  UP  UP  86 - 87 87 ± 1 2  71 - 88 82 ± 2 9  71 - 86 76 ± 2 9  -  91 - 110 101 * 4 9  88 - 111 98 ± 5 9  P = each c o n d i t i o n i n g d e p o l a r i z i n g command was p a i r e d with one s t i m u l a t i o n o f the t e s t stratum radiatum EPSP a t 1 msec f o l l o w i n g the onset o f the conditioning pulse. UP a c o n d i t i o n i n g d e p o l a r i z i n g commands were given alone and not p a i r e d t e s t input s t i m u l a t i o n .  with  - 55 -  Figure 9 Induction o f STP and LTP by p a i r e d c o n d i t i o n i n g d e p o l a r i z a t i o n o f a CA^ neuron. To evoke EPSPs i n the CAi neuron, b i p o l a r t e s t s t i m u l a t i n g e l e c trodes were p o s i t i o n e d i n stratum radiatum and stratum o r i e n s . A r e c o r d i n g i n t r a c e l l u l a r microelectrode i n the CAi neuron was used t o record the t e s t EPSPs (a.: the c a l i b r a t i o n s represent 10 msec and 5 mV) and to apply the c o n d i t i o n i n g d e p o l a r i z i n g commands (3-10 nA, 75-200 msec, 1-10 commands at 0.2 Hz) (fj: the square wave i s 0 .lnA and 75 msec). The s t i m u l a t i o n strengths were adjusted to evoke EPSPs at 30% o f maximum s i z e . The s t i m u l a t i o n o f stratum radiatum (every 15 seconds) and stratum o r i e n s (every 15 seconds) was arranged i n such a way that there was a 7.5 second delay between the two s t i m u l a t i o n s . During the unpaired c o n d i t i o n i n g d e p o l a r i z a t i o n (UC), the t e s t EPSPs by stratum o r i e n s and stratum radiatum were not evoked and during the paired c o n d i t i o n i n g d e p o l a r i z a t i o n (PC) the stratum radiatuminduced EPSP was evoked 1 msec a f t e r the onset o f the d e p o l a r i z i n g command while the stratum o r i e n s was not s t i m u l a t e d . When more than one UC or PC was a p p l i e d , they were given a t 0.2 Hz. Stratum radiatum s t i m u l a t i o n at 0.2 Hz without the presence o f the c o n d i t i o n i n g d e p o l a r i z a t i o n o f the CAi neuron d i d not r e s u l t i n a change i n the s i z e o f the EPSP ( r e s u l t s not shown). Note STP, and LTP o f the stratum radiatum-induced, but not o f the stratum oriens-induced, EPSP f o l l o w i n g the PC. In the graphs, EPSPs were recorded a t 30 second i n t e r v a l s . A f t e r UC and PC, however, recordings were taken at 15 second i n t e r v a l s f o r 3 minutes. The ' r e s t i n g ' membrane potent i a l o f the neuron at the beginning o f the experiment was -65 mV and a t the end o f the experiment was -61 mV. This i s a t y p i c a l experiment; s i m i l a r r e s u l t s were found i n s i x c e l l s . r  - 57 graded decrease in e x c i t a b i l i t y that p a r a l l e l e d the p o s t - t e t a n i c  potentia-  t i o n s in both time course and magnitude (amount of c u r r e n t to discharge as a % of c o n t r o l :  185 ± 6 SEM  at 60 seconds, post-5 t r a i n paired  cell condi-  t i o n i n g by radiatum, 6 of 7 expts., no change in 1 of 7; 138 ± 6 SEM at 60 seconds post-5 t r a i n paired c o n d i t i o n i n g by o r i e n s , 5 of 6 expts., no change in 1 of 6).  Tetanic t r a i n s to c o n d i t i o n i n g inputs in e i t h e r stratum  oriens  or stratum radiatum were able to induce the decrease in terminal e x c i t a b i lity.  Increasing the number of paired c o n d i t i o n i n g t r a i n s to ten led to a  prolonged  decreased in e x c i t a b i l i t y that was a s s o c i a t e d with LTP of the t e s t  EPSP (amount of c u r r e n t to discharge c e l l as a % of c o n t r o l :  154 ± 5 SEM at  15 minutes post-10 t r a i n paired c o n d i t i o n i n g by radiatum, 5 of 6 expts., change in 1 of 6) (Figure 8 ) .  no  A summary of a l l the r e s u l t s i s shown in  Table 3. 4.6  Temporal -requirements-for - induction-of-STP For these experiments, the number of p a i r e d c o n d i t i o n i n g  f i x e d at f i v e because t h i s paradigm was with no LTP.  trains  was  one that most r e l i a b l y induced  STP  Two parameters were v a r i e d here:  the order in which each t e s t  and c o n d i t i o n i n g inputs were paired and the i n t e r v a l between the two.  In  Figure 10, the x-axis i s the i n t e r s t i m u l u s i n t e r v a l between the onset of the c o n d i t i o n i n g t r a i n and the t e s t stimulus. i n d i c a t e that  the  t e s t stimulus  Negative i n t e r s t i m u l u s i n t e r v a l s  preceded the  onset  of the  conditioning  t r a i n s while p o s i t i v e i n t e r v a l s i n d i c a t e the duration between the onset the c o n d i t i o n i n g t r a i n and the succeeding  of  t e s t stimulus.  In the experiments where the t e s t stimulus succeeded the onset of the conditioning  tetanus,  there  was  s i g n i f i c a n t STP  up  to  an  interstimulus  - 58 -  Table 3 . E f f e c t s of p a i r e d and c o l l a t e r a l terminal e x c i t a b i l i t y .  unpaired  conditioning  t r a i n s on  Schaffer  60 s post-5 t r a i n s unpaired paired  15 min post-10 t r a i n s unpaired paired  stratum radiatum conditioning (threshold as a % of c o n t r o l )  98 ± 3 n = 7  185 ± 6 n = 6  99 ± 2 n = 7  stratum o r i e n s conditioning (threshold as a % of c o n t r o l )  99 ± 3 n = 6  138 ± 6* n = 5  * Results are expressed  as mean ±  SEM.  154 ± 5 n = 5  59  -  90  -  L-  i  -100  t  t  i  -80  -60  -40  i  i  i  -20 0 20 40 INTERSTIMULUS INTERVAL  60 (ms)  80  i  i  i  i  100  F i g u r e 10 The l i m i t s of the temporal r e l a t i o n s h i p between c o n d i t i o n i n g and t e s t stimuli f o r the i n d u c t i o n of a s s o c i a t i v e p o t e n t i a t i o n . The t e s t EPSP was evoked by s t i m u l a t i o n of stratum radiatum and the c o n d i t i o n i n g was achieved through s t i m u l a t i o n of stratum o r i e n s (5 t r a i n s , 10 pulses i n each t r a i n at 100 Hz, one t r a i n every 5 seconds). One t e s t stimulus was p a i r e d with each o f the f i v e c o n d i t i o n i n g t r a i n s at every i n t e r s t i m u l u s i n t e r v a l examined. The c o n d i t i o n i n g - t e s t i n t e r v a l was v a r i e d berween -100 to +100 ms. A negative delay i n d i c a t e s that the t e s t stimulus preceded the onset of the c o n d i t i o n ing t r a i n and a p o s i t i v e delay i n d i c a t e s the time a t which the t e s t populat i o n EPSP was evoked f o l l o w i n g the onset of the c o n d i t i o n i n g tetanus. Each point on the graph ( f i l l e d c i r c l e s ) represents mean ± SEM of the t e s t popul a t i o n EPSP magnitude measured at 1 minute post-5 paired t r a i n s . The one point represented by the f i l l e d diamond shows a s i g n i f i c a n t depression of the t e s t EPSP at 1 minute post-5 unpaired t r a i n s of stratum o r i e n s ( i . e . , t e s t EPSP was not evoked during c o n d i t i o n i n g ) , n i s shown i n parentheses above each p o i n t on the graph.  - 60 i n t e r v a l of 80 msec. The curve i s bimodal with a dip in the p o t e n t i a t i o n at the 40-50 msec i n t e r v a l .  Maximal p o t e n t i a t i o n was  induced  and c o n d i t i o n i n g s t i m u l i are a c t i v a t e d simultaneously. given to the c o n d i t i o n i n g stratum  when both t e s t  Unpaired t r a i n s were  oriens input to confirm non-overlap with  the t e s t input at stratum radiatum, as well as to show t h a t t e t a n i c c o n d i t i o n i n g t r a i n s alone did not induce STP. The amount of STP  induced  by r e v e r s i n g the order of the s t i m u l i  pears to drop o f f markedly with interval.  respect  to i n c r e a s i n g the  ap-  interstimulus  S i g n i f i c a n t p o t e n t i a t i o n was l i m i t e d to an i n t e r s t i m u l u s i n t e r v a l  of -50 msec.  The s i g n i f i c a n c e of these r e s u l t s are examined in the f o l l o w -  ing s e c t i o n .  5 DISCUSSION  The r e s u l t s show that STP and LTP in the hippocampal s l i c e can be i n duced a s s o c i a t i v e l y without t e t a n i c s t i m u l a t i o n of the p o t e n t i a t e d  pathway.  Studies in the current l i t e r a t u r e found a s s o c i a t i v e i n d u c t i o n of  potentia-  t i o n only in t e t a n i z e d pathways (Barrionuevo Levy and Steward, 1979;  and  McNaughton et- a l ; , 1978).  Brown, 1983;  Lee,  In the present  1983; experi-  ments, the synaptic response to a s i n g l e a f f e r e n t v o l l e y i s p o t e n t i a t e d f o r a v a r i a b l e duration when i t c o i n c i d e s with a c o n d i t i o n i n g t e t a n i z a t i o n given at a separate converging  a f f e r e n t pathway.  This c o i n c i d e n t a l s t i m u l a t i o n of  the s i n g l e a f f e r e n t v o l l e y must occur w i t h i n an asymmetrical temporal window around the c o n d i t i o n i n g  tetanus.  - 61 No attempt was made to subdivide the STP induced by the present method i n t o subcomponents such as augmentation and PTP, other systems (Magleby and nature  of tetanus-induced  Zengel, PTP  1975b, 1976a).  done with  STP  in  Like the homosynaptic  ( E c c l e s , 1953), o n l y that a f f e r e n t pathway  paired with  the c o n d i t i o n i n g stimulus  induced  increases  STP  as was  in amplitude  t r a i n s i n a manner s i m i l a r to PTP.  is potentiated.  This a s s o c i a t i v e l y  with the number of paired c o n d i t i o n i n g However, the duration of p o t e n t i a t i o n  does not seem to increase with the number of c o n d i t i o n i n g t r a i n s , a property that suggests  augmentation.  Since  only 1, 5 and  10 paired  conditioning  t r a i n s were examined, i t i s p o s s i b l e that the graded nature of the STP not f u l l y evident, e s p e c i a l l y i f the i n d u c t i o n of LTP  masked a  was  prolonged  duration of STP. Previous  studies of STP  squid g i a n t axon a l l concluded  in s p i n a l cord, neuromuscular j u n c t i o n  and  that STP was mediated p o s t - t e t a n i c a l l y v i a an  increase in t r a n s m i t t e r r e l e a s e (del C a s t i l l o and Katz, 1954c; Eccles  and  K r n j e v i c , 1959a, 1959b; L l o y d , 1949; Magleby and Zengel, 1975b; Takeuchi  and  Takeuchi, 1962).  In the hippocampus, where quantal a n a l y s i s of t r a n s m i t t e r  release  an equivocal  is s t i l l  locus of STP  procedure (Johnston  i s a l s o b e l i e v e d to be presynaptic  and  Brown, 1984),  the  (McNaughton, 1982;  Racine  In the present experiments where the c o n d i t i o n i n g e l e c t r o d e was  placed  and Mil gram, 1983).  in the same stratum as the t e s t e l e c t r o d e , there was the p o s s i b i l i t y of some undetected  i n t e r a c t i o n of p r e s y n a p t i c terminals which might account f o r the  post-conditioning potentiation. i n t e r a c t i o n s , as was suggested  This communication may  be through  ephaptic  f o r i n t e r a c t i o n s between somata and  dendrites  - 62 (Richardson  et.- - a l : ,  1984;  Turner  et- a l ; , 1984), e l e c t r o t o n i c coupling  (MacVicar and Dudek, 1981, 1982), the r e l e a s e of ions (Goh and S a s t r y , Weight and E r u l k a r , 1976) and S a s t r y , 1985).  or neurotransmitter  1985;  (Alger and T e y l e r , 1978;  Goh  However, the placement of the c o n d i t i o n i n g e l e c t r o d e i n  an a n a t o m i c a l l y separate stratum precludes the p o s s i b i l i t y t h a t the postc o n d i t i o n i n g e f f e c t s are  due  e n t i r e l y to p r e s y n a p t i c  terminal  or  fiber  i n t e r a c t i o n s , e s p e c i a l l y s i n c e no axoaxonic synapses have been found in t h i s area. from  Thus, i t i s i n t e r e s t i n g that the r e s u l t a n t a s s o c i a t i v e STP experiments  using  e l e c t r o d e s are remarkably  stratum  oriens  and  stratum  radiatum  and  conditioning  s i m i l a r . Without invoking h y p o t h e t i c a l e x c i t a t o r y  interneurons  or i n t e r - s t r a t a a s s o c i a t i o n a l pathways, the most l o g i c a l  diator  the  of  LTP  conditioning  effects  is  (McNaughton, 1982; McNaughton et a-1:, 1978;  the  postsynaptic  me-  CA-^  cell  Robinson and Racine, 1982).  i s evident that the p o s t s y n a p t i c c e l l i s capable of mediating  It  heterosynaptic  e f f e c t s , s i n c e unpaired stratum o r i e n s c o n d i t i o n i n g t r a i n s cause a heteros y n a p t i c depression of the EPSP to stratum radiatum F i g u r e 10).  Notwithstanding  t e s t s t i m u l a t i o n (see  the postsynaptic nature of heterosynaptic  p r e s s i o n (Dunwiddie and Lynch, 1978;  Lynch et-.- a l : , 1977;  1984), the point i s that a c t i v a t i o n of the CA^  de-  S a s t r y et a l ; ,  c e l l v i a the b a s i l a r den-  d r i t e s w i l l have an e f f e c t that can be observed at the a p i c a l d e n d r i t e s . The p i v o t a l r o l e of the p o s t s y n a p t i c c e l l in the present  experiments  i s in p a r t i a l agreement with the r e s u l t s of others who  nonetheless  that p o s t s y n a p t i c c e l l  f o r i n d u c t i o n of  spike discharge was  p o t e n t i a t i o n (Douglas, 1978; i o n i n g experiments  not necessary  Wigstrom et-al-. , 1982).  found  In the alveus c o n d i t -  (see Table 1), i t was a necessary c o n d i t i o n of antidromic  - 63 dromic  stimulation  that  the  intracellular depolarization  CA-^  cell  does s p i k e .  experiments, i t was  S i m i l a r l y , with  necessary  to use  the supra-  t h r e s o l d currents in order to induce a s s o c i a t i v e p o t e n t i a t i o n .  Lee  examined the  associative  a b i l i t y of antidromic  p o t e n t i a t i o n in the CA^ orthodromic tetanus  cell  and  alvear  tetanus  found that LTP  i s paired with an antidromic  conclude that postsynaptic  c e l l discharge  to  induce  (1983)  i s not enhanced when an train.  This  i s not e s s e n t i a l .  led him  A major d i f -  ference between that study and the present one i s that the former was  done  in normal p e r f u s i n g medium whereas the l a t t e r included 10 nm p i c r o t o x i n . the absence of p i c r o t o x i n , the r e c u r r e n t or feed-forward to the CA^ c e l l s would s u r e l y be a c t i v a t e d , thereby z a t i o n of the soma and probably the d e n d r i t e s .  shunting  be correspondingly  (1983) observed no  alvear  conditioning.  experimental  The  need f o r c e l l  schemes i s obvious  i n d u c t i o n i s at the subsynaptic  i f the  spike  adjacent  dendrite.  d e n d r i t i c s i t e would  discharge  initiating  enhancement in the  event f o r  zone in the d e n d r i t e s .  t i o n of a f f e r e n t s r e s u l t s in synaptic transmission the subsynaptic  the d e p o l a r i -  The p r o b a b i l i t y of a s u f f i -  the subsynaptic  Hence, Lee  with  present  associative  Orthodromic s t i m u l a -  that f i r s t l y  depolarizes  The e l e c t r o t o n i c spread of t h i s d e p o l a r i z a t i o n to  d e n d r i t i c s i t e s could be independent of c e l l spike discharge.  the present  In  i n h i b i t o r y neurons  c i e n t l y large d e p o l a r i z a t i o n reaching low.  to  s t u d i e s , where s i n g l e a f f e r e n t v o l l e y s are paired with  t i o n i n g t r a i n s , the subsynaptic  In  condi-  s i t e must be invaded by a s u f f i c i e n t l y large  d e p o l a r i z a t i o n f o r the i n i t i a t i n g event to occur.  Unlike orthodromic c o n d i -  t i o n i n g t e t a n i , the antidromic t e t a n i do not d e p o l a r i z e the dendrites f i r s t ; t h i s i s a l s o true of the i n t r a c e l l u l a r c u r r e n t i n j e c t i o n s .  In a d d i t i o n , the  - 64 v o l l e y s do not d e p o l a r i z e the dendrites s u f f i c i e n t l y f o r a s s o c i a t i v e tion.  Therefore,  i t i s essential  to a c t i v a t e  the CA-^ c e l l  t h r e s h o l d f o r an a c t i o n p o t e n t i a l , and to do so repeatedly with a tetanus to ensure that the decrementally  induc-  above the prolonged  propagated d e p o l a r i z a t i o n a c t u a l l y  invades the d e n d r i t e s . In agreement with the above l i n e o f reasoning i n t r a c e l l u l a r c u r r e n t i n j e c t i o n experiments. exaggerated need f o r the postsynaptic  are the r e s u l t s from  Indeed, there seems to be an  c e l l to f i r e a c t i o n p o t e n t i a l s ; the  l e f t i n s e t i n Figure 9 shows that the CA^ c e l l a c t u a l l y f i r e s with a d e p o l a r i z i n g current i n j e c t i o n ofO'.lnA f o r 75 msec.  repeatedly  Yet the c u r r e n t  i n j e c t i o n s needed to induce a s s o c i a t i v e STP and LTP were several orders of magnitude greater than the i n t e n s i t y needed to f i r e the c e l l .  This apparent  discrepancy can be e a s i l y explained i f one examines the premise f o r a s s o c i a t i v e p o t e n t i a t i o n , which r e q u i r e s that a number o f a f f e r e n t f i b e r s i n t e r a c t more or l e s s simultaneously. terminals  This means that a great number o f a f f e r e n t  —  and presumably subsynaptic  vated.  Since  the number of a c t i v a t e d  finite,  i t may be necessary  dendritic sites —  must be a c t i -  synapses t o any one CA-^ c e l l i s  t o d e p o l a r i z e the c e l l with several times the  t h r e s o l d current to ensure the d e p o l a r i z a t i o n of the maximum number o f dendritic  initiating  sites.  A l t e r n a t e l y , the maximum number o f  initiating  s i t e s on the dendrites o f one c e l l may be too small f o r a s s o c i a t i v e  induc-  t i o n , r e q u i r i n g the f i r i n g o f the CA-^ c e l l so that a d d i t i o n a l c e l l s  could  be r e c r u i t e d through ephaptic  i n t e r a c t i o n s (Richardson  et a l ; , 1984) or e l e c t r o t o n i c coupling  e t - a l ; , 1984; Turner  (MacVicar and Dudek, 1981, 1982).  Whatever the mechanism, i t i s c l e a r that the postsynaptic c e l l ( s ) i n i t i a t e s the i n d u c t i o n  - 65 of a s s o c i a t i v e p o t e n t i a t i o n but cannot be the only causal  event.  To induce a s s o c i a t i v e STP and LTP, the a f f e r e n t pathway must be l a t e d at l e a s t once i n conjunction with the c o n d i t i o n i n g stimulus. bly,  stimu-  Presuma-  the postsynaptic d e p o l a r i z a t i o n sets up a s y n a p t i c environment that i s  conducive  to p o t e n t i a t i o n .  It can be argued that the c r u c i a l  a s s o c i a t i v e p o t e n t i a t i o n occurs  at the  presynaptic  event  terminals;  s p e c i f i c i t y of the a s s o c i a t i v e l y - i n d u c e d p o t e n t i a t i o n supports Since the s i t e of the c o n d i t i o n i n g input i s inconsequential  the  for input  t h i s view. to which a f -  f e r e n t pathway i s p o t e n t i a t e d , the d e p o l a r i z a t i o n of the subsynaptic  site  can only be i n t e r p r e t e d as a g e n e r a l i z e d change i n the postsynaptic  cell,  namely the d e n d r i t e s .  Otherwise, subsequent s t i m u l a t i o n of any  pathway would have produced a p o t e n t i a t e d postsynaptic  response.  afferent This i s  c l e a r l y not the case. The e x c i t a b i l i t y changes of the S c h a f f e r c o l l a t e r a l terminals i n d i c a t e a c r i t i c a l r o l e f o r the presynaptic f i b e r .  P o s t - t e t a n i c p o t e n t i a t i o n at the  neuromuscular j u n c t i o n and s p i n a l cord i s accompanied by a p a r a l l e l of h y p e r p o l a r i z a t i o n at the presynaptic terminal Gasser and Grundfest,  1936;  Larrabee  (Gasser  and Bronk, 1938).  period  and Graham,  1932;  Upon reaching  the  h y p e r p o l a r i z e d t e r m i n a l , a presynaptic a c t i o n p o t e n t i a l would be r e l a t i v e l y l a r g e r in amplitude,  thereby r e l e a s i n g more t r a n s m i t t e r per a c t i o n p o t e n t i a l  (Eccles  and  Krnjevic,  1959a, 1959b; Hubbard  and  Schmidt,  1963;  Lloyd,  1949).  Another consequence of t h i s h y p e r p o l a r i z a t i o n i s a decrease  i n the  e x c i t a b i l i t y of the presynaptic terminal as defined by Wall (1958) (Wall and Johnson, 1958).  T h i s decreased e x c i t a b i l i t y i s a l s o observed  study (see Figure 4B, Table 3 ) .  i n the present  66  -  -  Note that only the paired c o n d i t i o n i n g t r a i n s produced any changes in e x c i t a b i l i t y of the that unpaired  Schaffer  c o l l a t e r a l terminals.  Equally  important  c o n d i t i o n i n g t r a i n s did not a l t e r e x c i t a b i l i t y , thereby  is reaf-  f i r m i n g the lack of l a s t i n g consequences due to any d i r e c t i n t e r a c t i o n s between the t e s t and c o n d i t i o n i n g inputs. lity  decrease i s r e a d i l y seen.  The  The graded nature of the e x c i t a b i p a r a l l e l between  e x c i t a b i l i t y changes and the a s s o c i a t i v e l y - i n d u c e d causal  relationship.  proportionate  volley.  and  LTP  terminal  suggests a  Assuming that the decreased e x c i t a b i l i t y r e f l e c t s a  hyperpolarization  hyperpolarization  STP  Schaffer  will  of the t e r m i n a l s , one  lead to increased  The r e s u l t s presented  a p l a u s i b l e presynaptic  transmitter  can  i n f e r that t h i s  r e l e a s e per  afferent  are f a r from c o n c l u s i v e , but they do suggest  mechanism f o r a s s o c i a t i v e l y - i n d u c e d  STP;  similar  decreases in a f f e r e n t terminal e x c i t a b i l i t y have been found to accompany LTP in the hippocampus (Sastry, 1982).  A d e f i n i t i v e quantal a n a l y s i s of potent-  iated t r a n s m i t t e r r e l e a s e in the hippocampus has yet to be done, but i n creased  quantal  during LTP  content  (Baxter  was  found i n the c r a y f i s h neuromuscular  et • al-;, 1985).  junction  However, the r e l a t i o n s h i p between pre-  synaptic changes and hippocampal LTP i s more tenuous. What f a c t o r or process  does the postsynaptic  does t h i s t r a n s l a t e i n t o a presynaptic the pre- and postsynaptic candidates. sium [ K ] +  Q  a l ; , 1980). tetanic  elements may  In the stratum may  reach  change  c e l l e l a b o r a t e , and  This e l u s i v e l i n k between  be one or more of several  pyramidale of f i e l d C A ^  a maximum of 12 mM  during  how  possible  e x t r a c e l l u l a r potas-  a tetanus  (Benninger et  Alger and T e y l e r (1978) found a good c o r r e l a t i o n between post-  e x t r a c e l l u l a r potassium  [K ] +  and  the  amplitude  of  the  poten-  - 67  tiated [K ]  CA-^ and  +  q  STP  population the  spike;  population  i s a t l e a s t one  order  no  EPSP.  -  such  correlation  However, the  of magnitude g r e a t e r  call  i n d u r a t i o n than the STP  stu-  vated  increases  Q  agreement w i t h  other  postsynaptic c e l l Gardner-Medwin, drites  the  mechanisms  of  suggesting  1976).  region  the  The  same  after  could  study  showed  a tetanus;  increase  such  terminal  tetanized  terminals  a  impasse can  underlying Of  Graham, 1932; bits  to  ionic  Sastry  at  +  Q  is  the  Fritz  and  the  den-  at  the  depolarization  (1985) found t h a t terminals  in  of  environment by  ele-  untetan-  actually exhibit  excitability.  This t h e o r e t i c a l  junctions.  adjacent  [K ]  excitability  ized  mechanism  cell  responsiveness  that  an  and  increased  postsynaptic  enhanced  r a t h e r than decrease i t . Indeed, Goh afferent  Their conclusion that  a f t e r t e t a n i c s t i m u l a t i o n (Abraham e t a l : , 1985;  i s also elevated  terminal  excitability  between they  would be more p r o p e r l y c a l l e d LTP.  +  found  potentiation that  d i e d here and [K ]  was  the  post-tetanic  two  a s s o c i a t i v e STP.  of  Grundfest,  several  1936), the  minutes,  which  T h i s second phase has  activated  electrogenic  Takahashi,  1966;  Rang  ouabain-sensitive  sodium  and  Na ,K -ATPase +  +  sodium  concentration  1972),  and  a  1968a,  1968b).  lesser It  at  peripheral  neuronal  was  is  correlates  +  on  found  that  phase e x h i -  with  that  and  elevated  both  The  dependent  (Ritchie an  (Nakajima  +  1968b).  directly  extent,  well  (Na ,K -ATPase)  1968a,  [Na ]^  second prolonged  and  of  been presumed t o be the r e s u l t o f  pump  Ritchie,  lular  to  hyperpolarization  ionic  phases of p o s t - t e t a n i c h y p e r p o l a r i z a t i o n (Gasser  Gasser and  duration  be surmounted by e x a m i n a t i o n o f the  activity upon  Straub, [K ] +  Q  (Rang  Na ,K -ATPase +  +  and  the  of  an and  this  intracel-  1957;  Thomas,  and  Ritchie,  post-tetanic  - 68  hyperpolarization (McDougal and and  rabbit  inorganic ically  exhibit  the  Osborn, 1976). vagus  nerve  -  same  Tetanic  increases  sigmoidal  an  exponential  S t r a u b , 1978).  The  increasing stimulus In  light  of  rate  rate of  Na ,K -ATPase +  +  constant  inorganic  depolarizes  the  lease  a  amount o f  potassium.  The  synaptic  drive  terminals;  to  in f a c t ,  activate the  terminals  by a s i n g l e a f f e r e n t v o l l e y may  terminals to that  and  afferents.  of The  p r o c e s s , such as or b e t t e r  nal,  that  this  process to  by  the  +  Na  axons.  This  transmitter  hyperpolarization an  increase  the  a state  impulse.  the  influx,  thereby  hyperpolarization  and with  may  intracelwhich [K ]  re-  Q  does  test  pre-  +  the  may  be  i n v a s i o n of  inthese  +  hyperpolarizing would be  afferent fibers,  leading  the  number  presumably  await of  of  a the  (Hubbard,  a c t i o n p o t e n t i a l t o the  a c t i v a t i o n to  to  event f o r some o t h e r  of a v a i l a b l e t r a n s m i t t e r  hyperpolarization  the  analogous  subsequent t e s t s t i m u l a t i o n s  pool  Increasing  at  by  STP  +  to  subliminal  of  in  terminals  i s merely the p r i m i n g  i n the  Q  induce an exaggerated N a , K -  +  potentiation; of  increase  e x c i t a b i l i t y , the  p r o p a g a t i o n of a p r e t e r m i n a l  mediates  afferent  release  increases  dendrites,  +  of  (Ritchie  t e t a n u s or  Na ,K -ATPase  induced by t e t a n i c s t i m u l a t i o n o f the  facilitation  1963)  consequent  preterminal  transient  excitability  During t h i s phase of i n c r e a s e d  the  +  post-tetan-  induction  postsynaptic  the  creased.  ATPase response t o  also  a conditioning  injection  enough  [K ]  measured  minutes  associative  current  exert  about 4  the  lular  not  of  S t r a u b , 1978).  mechanism,  as  to r e s t i n g l e v e l s  phosphate e f f l u x  i n v o l v e the f o l l o w i n g s e r i e s o f e v e n t s :  large  activity  f r e q u e n c y ( R i t c h i e and above  on  s t i m u l a t i o n of g a r f i s h o l f a c t o r y nerve  phosphate e f f l u x , which then r e t u r n s  with  dependence  termielevates  supra-activation  paired  conditioning  - 69 t r a i n s or c u r r e n t  i n j e c t i o n s i n t o CA-^  neurons could  increase the  [K ] +  Q  so as to r e c r u i t more presynaptic terminals to the s u b l i m i n a l l e v e l of a c t i vation.  The  expression  of  the  potentiated  release  would  then  follow  mechanisms along the l i n e s of the r e s i d u a l calcium theory (Katz and M i l e d i , 1968). I t must be borne in mind that the h y p e r p o l a r i z a t i o n i s i n f e r r e d from the decreased terminal e x c i t a b i l i t y and, i t i s p o s s i b l e to have an decrease  i n e x c i t a b i l i t y without  d e p o l a r i z a t i o n , such  as that  hyperpolarization.  induced  by  For example, a small  a s l i g h t l y elevated  lead to i n a c t i v a t i o n of voltage dependent sodium channels To generate  apparent  [K ] , +  Q  can  at the t e r m i n a l .  an antidromic a c t i o n p o t e n t i a l , a higher d e p o l a r i z i n g c u r r e n t  must be passed  to a c t i v a t e those a v a i l a b l e sodium channels  r i g h t at the t e r m i n a l .  Furthermore,  that are  the e x c i t a b i l i t y i t s e l f  not  is inferred  from higher c u r r e n t i n t e n s i t i e s needed to f i r e an antidromic a c t i o n potential.  The higher current may be needed to overcome an i n c r e a s e i n r e s t i n g  conductance of any one of several i o n s . Other p o s s i b l e mechanisms f o r the observed volve  calcium-activated  ( M a l l a r t , 1984; a l ; , 1984)  potassium  + +  at  S a s t r y , 1979), calcium-dependent  or voltage-dependent  periphery, C a  channels  calcium channels  i n d u c t i o n of STP may the  presynaptic  terminal  c h l o r i d e channels  (Owen et  (MacVicar,  1984).  f l u x e s at the presynaptic terminal during normal and  l i t a t e d t r a n s m i t t e r r e l e a s e has been well e s t a b l i s h e d (Hodgkin 1957; Katz and M i l e d i , 1967, 1968). Ca  + +  In the faci-  and Keynes,  Therefore, i t i s h a r d l y s u r p r i s i n g that  or C a - m e d i a t e d currents can be involved i n a s s o c i a t i v e STP. ++  workers have suggested  in-  the a c t i v a t i o n of a Ca  Some  -mediated p r o t e i n kinase C  - 70 in the presynaptic terminal to account  f o r LTP (Malenka et - - a l . , 1986b).  This kinase can be s e l e c t i v e l y a c t i v a t e d by c e r t a i n phorbol e s t e r s to produce LTP i n the hippocampus; the LTP thus produced cannnot be d i s t i n g u i s h e d from tetanus induced LTP, and n e i t h e r LTP can be induced when maximal potent i a t i o n has been achieved by e i t h e r method (Malenka et-al.-, 1986b). P r o t e i n kinase C i s found 1985)  i n p r e s y n a p t i c t e r m i n a l s ( G i r a r d et- a l ; ,  and may c a t a l y z e the phosphorylation  (Nelson and Routtenberg, pyramidal  o f several p r o t e i n s during LTP  1985, Browning e t a l ; , 1979).  In the hippocampal  c e l l , c e r t a i n phorbol e s t e r s can block a C a - m e d i a t e d ++  c u r r e n t (Malenka e t - a l ; , 1986a); s i m i l a r channels  have been found  synaptic nerve terminals (Bartschat and B l a u s t e i n , 1985). t h i s outward K to  a prolonged  +  potassium i n pre-  The blockade of  conductance could delay membrane r e p o l a r i z a t i o n and lead Ca  + +  c u r r e n t , which would  increase  transmitter  release.  S i m i l a r l y , the delayed r e p o l a r i z a t i o n may prolong sodium channel i n a c t i v a t i o n , r e s u l t i n g i n an apparent decrease i n terminal e x c i t a b i l i t y . t i o n , there i s evidence  that phorbol  In a d d i -  e s t e r s increase calcium c u r r e n t s by  some a c t i o n on p r o t e i n kinase C (DeRiemer e t a l ; , 1985).  However, phorbol  e s t e r s do not induce p o s t - t e t a n i c p o t e n t i a t i o n independently o f LTP (Malenka e t - a l ; , 1986b). C o l l i n g r i d g e (1985) has proposed  a postsynaptic inward c u r r e n t to ac-  count f o r LTP. This hypothesis i n v o l v e s a glutatmate r e c e p t o r subtype, the s o - c a l l e d N-methyl-D-aspartate (NMDA) r e c e p t o r located on the p o s t s y n a p t i c dendrites (Baudry and Lynch, 1981). ent magnesium ( M g ) blockade ++  I t i s suggested  that a voltage depend-  o f a NMDA-receptor coupled  l i f t e d upon d e p o l a r i z a t i o n o f the p o s t s y n a p t i c c e l l  conductance i s  (Mayer et - a-1., 1984;  - 71 Nowak et - al.-, 1984). mate (Storm-Mathisen,  Subsequent r e l e a s e o f t r a n s m i t t e r , presumably g l u t a 1977), from the presynaptic terminal  greater l a t e c u r r e n t through  the NMDA receptor-coupled  ther enhance the postsynaptic response Gustafsson, 1984, 1985b).  then  causes  i o n channel  a  to fur-  ( H a r r i s et- a l ; , 1984; Wigstrom and  This inward c u r r e n t i s blocked by the NMDA anata-  g o n i s t 2-amino-5-phosphonovalerate (APV), which a l s o blocks the i n d u c t i o n o f LTP (Col 1 i n g r i d g e e t - a l ; , 1983; H a r r i s e t a l , 1984; Wigstrom and Gustafsson, 1984).  This mechanism thus accounts  f o r the need t o d e p o l a r i z e the post-  s y n a p t i c c e l l f o r a s s o c i a t i v e i n d u c t i o n o f LTP. The presynaptic element could be a c t i v a t e d by p o s s i b l e for  glutamate  autoreceptors  (Col 1 i n g r i d g e e t al-.-, 1983; McBean and Roberts,  1981). I f  these autoreceptors are a l s o NMDA r e c e p t o r s , then p r e s y n a p t i c d e p o l a r i z a t i o n ++  by  the a f f e r e n t v o l l e y may be r e q u i r e d  before  current flow can occur.  channels act  t o remove the Mg  Assuming that C a  (Dingledine, 1983a, 1983b), the e x t r a C a  as the r e s i d u a l C a  ter r e l e a s e .  + +  + +  + +  flows  inhibition through  these  i n the terminal would  i n Katz and M i l e d i ' s (1968) theory f o r t r a n s m i t -  Again, the increased conductance may shunt the e x t r a c e l l u l a r  c u r r e n t i n j e c t i o n s , thereby n e c e s s i t a t i n g higher current i n t e n s i t i e s t o f i r e an antidromic a c t i o n p o t e n t i a l . A f t e r the c o n c l u s i o n o f the present s t u d i e s , Wigstrom e t a l ; (1986) published a paper examining the a s s o c i a t i v e i n d u c t i o n o f LTP using i n t r a c e l l u l a r d e p o l a r i z a t i o n i n conjunction with authors  agree  t h a t the l e v e l o f p o s t s y n a p t i c c e l l  than spike a c t i v i t y , i s the determinant induce LTP.  single afferent volleys.  These  depolarization, rather  f a c t o r at the p o s t s y n a p t i c c e l l t o  However, they propose a p o s t s y n a p t i c locus f o r the induction o f  - 72 LTP based on t h e v o l t a g e - s e n s i t i v e NMDA r e c e p t o r - a c t i v a t e d current (Wigstrom et- - a l ; ,  1985).  stimulation Gustafsson,  or a b r i e f  i s apparent a f t e r a s i n g l e high  tetanus  (Wigstrom  et-al.,  intensity  1985; Wigstrom and  1984), and i s blocked by the NMDA antagonist 2-amino-5-phosphono-  v a l e r a t e (APV). tic  This current  In t h e i r scheme o f events, d e p o l a r i z a t i o n o f the subsynap-  membrane containing  NMDA r e c e p t o r s ,  i n conjunction  with  transmitter  released by a f f e r e n t s t i m u l a t i o n , i s t h e a s s o c i a t i v e event t h a t r e s u l t s i n p o t e n t i a t e d postsynaptic responses. This i s a very a t t r a c t i v e hypothesis, that the c o n d i t i o n i n g separated  tetanus  f o r these authors  also showed  and the s i n g l e a f f e r e n t s t i m u l a t i o n can be  by a period o f 40 msec (Wigstrom and Gustafsson,  1985b).  This  temporal separation can be a t t r i b u t e d t o a r e s i d u a l c u r r r e n t passing through the NMDA receptor channel and having  a time course o f about 50 msec f o r a  s i n g l e v o l l e y . (Wigstrom e t al.-, 1985).  These authors  suggest t h a t a temp-  oral overlap o f the NMDA c u r r e n t with the c o n d i t i o n i n g tetanus for  associative induction.  Such a mechanism would explain, the present ob-  s e r v a t i o n that a t e s t stimulus msec and s t i l l  i s essential  can precede the c o n d i t i o n i n g tetanus  induce STP. S i m i l a r l y , a c o n d i t i o n i n g  tetanus  expected t o generate a current o f longer duration; hence, t h e t e s t can f o l l o w a c o n d i t i o n i n g tetanus The  greatest  by up t o 80 msec and s t i l l  amount o f p o t e n t i a t i o n  conditioning stimulations.  i s induced  by 50  would be stimulus  produce STP.  by simultaneous t e s t and  Other workers have a l s o found that t h e a s s o c i a -  t i v e i n d u c t i o n o f LTP r e q u i r e s temporal overlap  o f t e s t and c o n d i t i o n i n g  s t i m u l a t i o n s (Kelso and Brown, 1986; Levy and Steward, 1983).  - 73 -  Wigstrom and Gustafsson's  theory f o r the a s s o c i a t i v e i n d u c t i o n of LTP  (1985b) does not account f o r the decreased terminal e x c i t a b i l i t y i n the present study.  This decrease i n terminal  e x c i t a b i l i t y i s an important  between STP i n the hippocampus and that i n other systems.  link  Although hyper-  p o l a r i z a t i o n o f the Schaffer c o l l a t e r a l terminals and a c c e l e r a t e d Na ,K ATPase a c t i v i t y was not demonstrated d i r e c t l y i n the present  study,  their  reported r o l e s i n PTP at other e x c i t a b l e j u n c t i o n s suggest equivalent r o l e s in the hippocampus. —  With respect to the temporal l i m i t s o f a s s o c i a t i v e STP  namely the 40 msec separation between a t e s t stimulus and the succeeding  c o n d i t i o n i n g tetanus, i t i s conceivable that each a f f e r e n t v o l l e y induces an increment of subliminal a c t i v a t i o n at the presynaptic t e r m i n a l , much as each a f f e r e n t v o l l e y induces  an inward c u r r e n t mediated by the NMDA  channel.  This increment o f subliminal a c t i v a t i o n could be t r i g g e r e d by the t r a n s i e n t + + increase  ++  i n Na ,K -ATPase  tage dependent channels,  a c t i v i t y or i n t r a c e l l u l a r Ca  vol-  but only i f a t e t a n i c d e p o l a r i z a t i o n of the post-  synaptic c e l l occurs within a short time. subliminal  through  Since the exact nature o f t h i s  a c t i v a t i o n i s unknown, any number o f p o s s i b i l i t i e s could  be  advanced. Notwithstanding  t h i s u n c e r t a i n t y , the r e s u l t s i n t h i s t h e s i s s t r o n g l y  support a c r u c i a l presynaptic event f o r the a s s o c i a t i v e i n d u c t i o n of STP as well as LTP.  Up u n t i l now, STP and LTP i n the hippocampus have been con-  sidered t o t a l l y separate phenomena.  The proposed d e n d r i t i c i n i t i a t i o n s i t e  f o r the a s s o c i a t i v e i n d u c t i o n of STP i s unusual because STP has already been shown t o be a presynaptic event a t other neuronal  junctions.  Furthermore, a  s i n g l e s t i m u l a t i o n o f a f f e r e n t s has not p r e v i o u s l y been shown to induce any  -  short-term  74  synaptic e f f i c a c y changes.  -  On  the  other  hand, a s s o c i a t i v e l y  induced STP i n the hippocampus may be due to a postsynaptic mechanism i n v o l v i n g NMDA receptor a c t i v a t i o n as suggested Wigstrb'm and Gustafsson,  1985b).  f o r LTP  (Col 1ingridge,  With respect to LTP,  1985;  a great number of  hypotheses regarding i t s mechanism focus on the p o s t s y n a p t i c c e l l f o r both i n d u c t i o n and maintenance.  Although there i s evidence f o r increased t r a n s -  m i t t e r r e l e a s e during LTP (Dolphin et a l ; , 1982;  Lynch e t - a l . - , 1985;  and Malthe-St&renssen,  1981), a p l a u s i b l e i n t e r a c t i o n between pre- and  synaptic  only  1985b).  cells  has  just  been  advanced  (Wigstrom  and  Skrede post-  Gustafsson,  Unfortunately, even t h i s l a s t hypothesis ignores the p o s s i b l e r o l e  of presynaptic causal events such as the l a s t i n g decrease  in S c h a f f e r c o l -  l a t e r a l terminal e x c i t a b i l i t y , which i s a s u b s t a n t i a l l i n k between LTP  and  presynaptic changes. The  present r e s u l t s a l s o suggest  s i t e f o r LTP.  a p o s s i b l e postsynaptic  initiating  This evidence i n d i c a t e s s i m i l a r c o n d i t i o n s underlying the two  forms of p o t e n t i a t i o n and suggests a common mechanism of i n d u c t i o n and maintenance.  The f a c t that a s s o c i a t i v e LTP can be induced i n the same f a s h i o n  as STP r a i s e s i n t e r e s t i n g p o s s i b i l i t i e s regarding the locus of each  poten-  t i a t i o n ; perhaps a s s o c i a t i v e STP i n the hippocampus (or c e n t r a l nervous system)  i s uniquely d i f f e r e n t from that in the periphery and  tetanus-induced  STP; there i s a l s o the p o s s i b i l i t y that some fundamental u n i t of p o t e n t i a t i o n i s r e s p o n s i b l e f o r both a s s o c i a t i v e STP and LTP, the d i f f e r e n c e between the two being only a matter of d u r a t i o n .  - 75 6 CONCLUSIONS Ever since B l i s s and Gardner-Medwin (1971) f i r s t reported LTP hippocampus, the working hypothesis  f o r LTP  not share a basic mechanism with  STP  in the  has always been that LTP  (Bliss  and  L0mo, 1973;  does  McNaughton,  1982; Abraham e t - a l ; , 1985); the former i s b e l i e v e d by some i n v e s t i g a t o r s to have a postsynaptic locus, the l a t t e r a presynaptic recent  f i n d i n g s that a s s o c i a t i v e  pre- and postsynaptic  induction  locus.  of LTP  In s p i t e of the  depends on  a c t i v i t y , the study of synaptic  coincident  potentiation  hippocampus remains l a r g e l y focussed on the postsynaptic c e l l .  The  in the present  study shows that STP can a l s o be induced by a s s o c i a t i v e i n t e r a c t i o n s between the pre- and duration  postsynaptic  that p a r a l l e l  cells.  This  a presynaptic  STP  demonstrates a magnitude  and  decrease in e x c i t a b i l i t y , which  has  been shown to accompany STP in other s y n a p t i c j u n c t i o n s .  A novel f i n d i n g i s  that STP and LTP can be induced without t e t a n i c s t i m u l a t i o n of the a f f e r e n t fibers.  By i n c r e a s i n g the number of i n t e r a c t i o n s between the pre- and  post-  synaptic  elements, greater  such  STP  can  be  i n t e r a c t i o n s , STP i s followed by LTP. ing tetanus  induced.  With ten  p a i r s of  The s i t e of a c t i o n of the c o n d i t i o n -  i s narrowed to the postsynaptic  c e l l ; the c o n d i t i o n i n g  effect  i t s e l f i s shown to be analogous to a g e n e r a l i z e d d e p o l a r i z a t i o n of the posts y n a p t i c c e l l and can be mimicked by i n t r a c e l l u l a r i n j e c t i o n s of d e p o l a r i z ing c u r r e n t .  Temporal separation  between the  a c t i v a t i o n of the pre- and  postsynaptic c e l l s was examined, and p o s s i b l e mechanisms f o r the changes were suggested. confined  These f i n d i n g s suggest that STP  to the presynaptic  terminals  and may  presynaptic  induction i s not  share a common a s s o c i a t i v e  - 76 i n d u c t i o n with LTP.  Conversely, LTP may  have  a very strong p r e s y n a p t i c  component f o r i n d u c t i o n and maintenance.  7 REFERENCES  ABRAHAM, W. C , BLISS, T. V. P. and GODDARD, G. V. (1985). 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