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New players tip the scales in the balance between excitatory and inhibitory synapses Levinson, Joshua N; El-Husseini, Alaa Mar 23, 2005

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ralssBioMed CentMolecular PainOpen AcceReviewNew players tip the scales in the balance between excitatory and inhibitory synapsesJoshua N Levinson and Alaa El-Husseini*Address: Department of Psychiatry, The Brain Research Centre, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, CanadaEmail: Joshua N Levinson - josh.levinson@mail.mcgill.ca; Alaa El-Husseini* - alaa@interchange.ubc.ca* Corresponding author    AbstractSynaptogenesis is a highly controlled process, involving a vast array of players which include celladhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteinsassociated with the synaptic vesicle machinery. These molecules cooperate in an intricate manneron both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts.This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputsbut virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucialaspect of synapse formation is whether a nascent synapse will develop into an excitatory orinhibitory contact. The tight control of a balance between the types of synapses formed regulatesthe overall neuronal excitability, and is thus critical for normal brain function and plasticity.However, little is known about how this balance is achieved. This review discusses recent findingswhich provide clues to how neurons may control excitatory and inhibitory synapse formation, withfocus on the involvement of the neuroligin family and PSD-95 in this process.In the brain, excitatory and inhibitory synaptic transmis-sion is mainly mediated by two neurotransmitters: gluta-mate which is released at excitatory glutamatergic synapticcontacts, and γ-amino butyric acid (GABA) which isreleased at inhibitory GABAergic synapses. Neural infor-mation processing is believed to be mediated by integra-tion of excitatory and inhibitory synaptic inputs [1-3].Therefore, precise controls must exist to maintain anappropriate number of one type of synaptic input relativeto the other. This process is thought to be governed byhomeostatic feedback mechanisms, however factorsinvolved remain elusive [4,5]. Impressive work carried outin recent years has begun to address the roles of moleculesinvolved in synapse formation. A theme that has emergedteins on the postsynaptic side. The major challenge in thisfield now is to understand how this molecular machineryis involved in synapse formation and specificity.What controls excitatory synapse development?The discovery of a protein complex that regulates postsy-naptic glutamate receptor clustering and the formation ofdendritic spines has revealed some of the mechanismsinvolved in excitatory synapse development. Two maingroups of key regulators of excitatory synapse formationhave been identified, namely postsynaptic scaffoldingproteins and cell adhesion molecules (CAMs). In the firstgroup, several proteins including members of the PSD-95family, shank, and homer have been shown to promotePublished: 23 March 2005Molecular Pain 2005, 1:12 doi:10.1186/1744-8069-1-12Received: 08 March 2005Accepted: 23 March 2005This article is available from: http://www.molecularpain.com/content/1/1/12© 2005 Levinson and El-Husseini; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 6(page number not for citation purposes)from these studies is that glutamatergic and GABAergicsynapses consist of complex, yet distinct networks of pro-excitatory synapse maturation (reviewed in [6]). Muchwork has focused on postsynaptic density protein-95Molecular Pain 2005, 1:12 http://www.molecularpain.com/content/1/1/12(PSD-95), one of the most abundant proteins in the PSD[6]. PSD-95 clustering at synapses occurs early in develop-ment, prior to other postsynaptic proteins [7], and discslarge, a Drosophila homolog of PSD-95, is required for nor-mal neuromuscular junction development in larva [8]. Inaddition, PSD-95 enhances AMPA-type glutamate recep-tor clustering and activity through interaction with star-gazin [9,10]. The second group, CAMs, have long beenimplicated in the formation of cell-cell contact, howeverthe roles of CAMs in the initiation and stabilization ofexcitatory synaptic contacts have only recently been dis-covered [11]. CAMs interact transsynaptically throughhomophilic interactions, such as in the case of SynCAM 1and protocadherins, or through heterophilic binding,such as with neuroligin and its binding partner, β-neu-rexin. It remains unresolved whether different sets ofCAMs cooperate to modulate synaptic stability andspecificity.New players in inhibitory synapse formationAlthough much progress has been made with respect tofactors involved in the formation of excitatory synapses,molecules that control inhibitory synapse formation haveremained largely unknown. Gephyrin, a scaffolding pro-tein enriched at inhibitory synapses, is one of a smallnumber of proteins that modulate GABA receptor cluster-ing [12]. Also, the neural CAMs L1, dystroglycan and L-CAM have been indirectly implicated in the establishmentof inhibitory synapse formation, however further work isneeded to clarify their involvement in this process [13-15].New findings from Prange et al. (2004) shed some lighton the involvement of members of the neuroligin (NLG)family of adhesion molecules in inhibitory synapse for-mation [16]. Unexpectedly, overexpression of NLG1induced not only excitatory synapses but also robustlyincreased the number and size of inhibitory presynapticterminals. The effect on inhibitory synapses was notrestricted to NLG1, as NLG2 and NLG3 were capable ofinducing similar effects on both excitatory and inhibitorypresynaptic terminals (an example of the effects of NLG2can be seen in Fig. 1A) [17]. Similar results were recentlyreported by Chih et al. (2005) [18]. If this is physiologi-cally relevant, one would expect members of the NLGfamily to be localized at both excitatory and inhibitorysynapses. Indeed, work done by Brose and co-workers wasthe first to resolve part of this mystery, reporting thatNLG2 is concentrated at inhibitory synapses [19]. Laterstudies reported similar observations on the enrichmentof NLG2 at inhibitory synapses [17,18,20]. This is in con-trast to NLG1, which is enriched at excitatory synapses[21].Neuroligins, β-neurexin, and PSD-95 modulate excitatory and inh bitory synapse formationFig re 1Neuroligins, β-neurexin, and PSD-95 modulate excitatory and inhibitory synapse formation. An example of the effects of a member of the neuroligin (NLG) family, NLG2 (green), on synapse formation. (A) Expression of NLG2 in hippocam-pal neurons increases the number of excitatory (VGLUT-positive; red) and inhibitory (VGAT-positive; blue) presynap-tic contacts. (B) Interfering with β-neurexin and NLG2 cou-pling blocks NLG2 (green)-mediated effects on inhibitory synapse formation. Treatment with a soluble form of β-neu-rexin decreases the number of sites positive for VGAT (blue). (C) NLG2 (red) is normally localized at inhibitory syn-aptic contacts (VGAT-positive; blue; upper panel). Overex-pression of PSD-95 shifts NLG2 from inhibitory to excitatory (PSD-95-positive; green) synapses (colocalization of NLG2 Page 2 of 6(page number not for citation purposes)and PSD-95 appears in orange; lower panel).Molecular Pain 2005, 1:12 http://www.molecularpain.com/content/1/1/12How do neuroligins mediate excitatory and inhibitory synapse formation?NLG1 was originally identified as a binding partner of thepresynaptic cell adhesion molecule, β-neurexin, which isknown to be coupled to a presynaptic protein complex[22-24]. Thus, coupling of NLGs to β-neurexin may acti-vate an array of molecular responses leading to the struc-tural reorganization of the presynaptic compartment. Insupport of this, a soluble form of β-neurexin blocks theformation of presynaptic terminals induced by heterolo-gously expressed NLG1 [25]. Another important findingby Graf et al. (2004) showed that β-neurexin expressed innon-neuronal cells or coupled to beads is sufficient toinduce the differentiation of inhibitory postsynaptic sites[20]. These results are further supported by experiments inhippocampal neurons which showed that inhibitory syn-apses induced by NLG1 and NLG2 can be blocked by sol-uble β-neurexin [17]. An example of the effects of solubleβ-neurexin on NLG2-mediated inhibitory synapse forma-tion is shown in Fig. 1B. Together, this provides a novelmechanism for inhibitory synapse formation mediatedthrough NLG-β-neurexin coupling. However, it remainsunclear how the interaction between NLGs and β-neu-rexin regulate synapse specificity since, β-neurexin canmediate the formation of both excitatory and inhibitorysynapses.Controlling the balance between excitatory and inhibitory synapsesA critical finding depicted from recent work by Prange etal. (2004) shows that association of NLGs with scaffold-ing proteins may control the balance between excitatoryand inhibitory synapses [16]. PSD-95 is known to bindNLG1 and recruit it to synapses via its PSD-95/Dlg/ZO-1homology (PDZ) domain [22,26,27]. As described above,expression of NLG1 alone induces the formation of bothexcitatory and inhibitory synapses. However, when coex-pressed with PSD-95, NLG1 effects were restricted to exci-tatory synapses. Another intriguing finding is thatoverexpression of PSD-95 redistributes endogenousNLG2 from inhibitory to excitatory synapses (Fig. 1C)[17]. Presumably this occurs through association with theC-terminal PDZ-binding motif in NLG2. This correlateswith the observation that PSD-95 overexpressionenhances formation of excitatory synapses with a corre-sponding decrease in inhibitory synapse formation [16].Such effects resulted in an overall increase in the excitatoryto inhibitory (E/I) synapse ratio. A recent study by Chih etal. (2005) further supports the notion that NLGs areinvolved in regulating the E/I ratio [18]. Knockdown ofNLGs, either individually or collectively, results in a sub-stantial decrease in inhibitory synaptic transmission, withrelatively little effect on transmission at excitatory syn-The changes observed upon manipulation of the levels ofPSD-95 and NLGs provide new clues to the mechanismsinvolved in controlling the E/I ratio. Thus, a new modelemerges; factors that regulate expression and stoichiome-try between cell adhesion molecules and scaffolding pro-teins may be central to the formation of excitatory andinhibitory synapses and the control of E/I ratio (Fig. 2). Inthis model, all members of the NLG family can induceboth excitatory and inhibitory synapses. However, PSD-95, and possibly other postsynaptic scaffolding proteinsregulate targeting and/or retention of specific NLGs to aparticular synaptic site, controlling which synapse type isinduced by which NLG family member. This may there-fore create a situation in which scaffolding proteins coop-erate or compete with one another for directing individualmembers of the NLG family to a specific synapse type.Implications in neurodevelopmental abnormalitiesSeveral physiological and pathological paradigms alterthe levels of PSD-95. For example, PSD-95 associationwith the PSD is dynamic and is regulated by synapticactivity and palmitate cycling on PSD-95 [28]. Synapticactivity also upregulates PSD-95 expression through aneuregulin mediated pathway [29]. In contrast, adminis-tration of cocaine, a drug known to cause hyperexcitabil-ity, results in down regulation of PSD-95 in the striatum,a region mainly composed of inhibitory neurons [30].Moreover, mutation of FMRP, a gene associated with frag-ile X mental retardation, results in a loss of regulation ofPSD-95 expression [31]. The following question arises:Are alterations in the levels of certain postsynaptic scaf-folding proteins or cell adhesion molecules sufficient tomanipulate the E/I synapse ratio? One would expect thatparadigms that interfere with proper assembly or expres-sion of proteins that control E/I ratio may have drasticeffects on synaptic balance if these changes occur during aperiod of active synapse formation.A change in the E/I synapse balance has been proposed tobe affected in many neurodevelopmental psychiatric dis-orders, including autism and some forms of mental retar-dation [32]. In particular, it is thought that autism isassociated with enhanced E/I neurotransmission due toeither increased excitation or reduced inhibition, and thatthis enhanced excitability leads to disruption of memoryformation and abnormal social behaviour associated withthis disorder. A potential defect in E/I ratio in autism andrelated disorders is emphasized by the recent discoverythat frame shift mutations in the NLG3 and NLG4 genes,which result in early protein truncation and misfolding,are associated with autism [33-36]. In addition, chromo-somal rearrangements in regions that harbor the NLG1,Page 3 of 6(page number not for citation purposes)apses, thus altering the E/I synaptic balance. NLG2 and PSD-95 genes have also been implicated inautism [37-39]. The potential involvement of NLG genesMolecular Pain 2005, 1:12 http://www.molecularpain.com/content/1/1/12Relative levels of scaffolding proteins and cell adhesion molecules control the balance between excitatory and inhibitory syn ps sFigure 2Relative levels of scaffolding proteins and cell adhesion molecules control the balance between excitatory and inhibitory syn-apses. NLGs and PSD-95 are used here as an example to demonstrate this concept. Under normal conditions, NLG1 is enriched at excitatory contacts whereas NLG2 is concentrated at inhibitory synapses. PSD-95 retains the majority of NLG1 at excitatory synaptic sites, whereas NLG2 localization is primarily controlled through interaction with an unknown scaffolding protein specific to inhibitory synapses. An increase in the levels of PSD-95 results in a shift of NLG2 molecules from inhibitory to excitatory synapses, presumably through PDZ-mediated binding to PSD-95. The resulting effect is an overall increase in the number of excitatory relative to inhibitory synapses, and thus an enhanced excitatory to inhibitory (E/I) synaptic ratio (for sim-plicity, changes in synapse number are indicated by changes in the size of the illustrated presynaptic terminals). An altered E/I ratio may result in defects in brain circuitry associated with behavioral and cognitive abnormalities such as those linked to psy-Page 4 of 6(page number not for citation purposes)chiatric, pain response, and learning and memory disorders.Molecular Pain 2005, 1:12 http://www.molecularpain.com/content/1/1/12as well as PSD-95 in autism therefore provides a possiblemolecular basis for this imbalance in E/I ratio, whichmanifests itself as abnormalities in patients affected withneurodevelopmental psychiatric disorders. Despite theseexciting observations however, recent genetic screens sug-gest that mutations in NLGs are fairly rare in autism[40,41]. Therefore, it is more likely that neurodevelop-mental psychiatric disorders may result from abnormalexpression of a diverse set of genes with functions relatedto those of NLGs and PSD-95. In the adult brain, forma-tion of new synaptic contacts is far less common, and thusCAMs and scaffolding proteins may be involved in con-trolling synaptic activity rather than synapse number.Alterations in the amounts of these proteins may thereforeresult in weakening or strengthening of either excitatoryor inhibitory synaptic activity and in turn modulate the E/I balance.ConclusionNew findings provide evidence for a potential mechanismthat controls the development of excitatory and inhibitorysynapses, which at least partially involves synaptic celladhesion and scaffolding molecules, among which are theNLG family of proteins and PSD-95. The levels of certainpostsynaptic molecules relative to others appears to con-trol the balance between different synapse types, and thusgeneration of a specific E/I ratio. This has importantimplications in neurodevelopmental disorders. To furtherunderstand how the E/I synaptic balance is establishedand maintained, it will be essential to address otherissues. For instance, is synaptic activity involved in thisprocess? If so, processes ranging from learning and mem-ory to nociceptive transmission in the spinal cord, both ofwhich are linked to neuronal activity, may be tied to con-trol of E/I balance. To what extent does cross-talk betweenthe pre- and postsynaptic sides play a role? At what devel-opmental stage is this balance first established, and whendoes its stabilization occur? Despite these questionswhich remain unanswered so far, a staggering amount ofprogress has been made in this field in recent years.Surely, the excitement generated from this progress willlead to a more complete understanding of control of syn-aptic balance in the years to come.List of abbreviationsPSD-95, postsynaptic density protein-95; PDZ, PSD-95/Dlg/ZO-1 homology; NLG, neuroligin; GABA, γ-aminobutyric acid; CAM, cell adhesion molecule; VGLUT, vesic-ular glutamate transporter; VGAT, vesicular GABAtransporter.AcknowledgementsWe thank Kimberly Gerrow and Rochelle Bruneau for their comments on the manuscript. AEH is a CIHR New Investigator, an MSFHR scholar and is References1. Fried SI, Munch TA, Werblin FS: Mechanisms and circuitryunderlying directional selectivity in the retina. Nature 2002,420:411-414.2. Schummers J, Marino J, Sur M: Synaptic integration by V1 neu-rons depends on location within the orientation map. Neuron2002, 36:969-978.3. 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