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Characterization of somatostatin receptor in rat/mice brain : implication in Huntington's disease

University of British Columbia

Somatostatin (SST) is a multifunctional peptide present in most brain regions as well as in peripheral organs. In QUIN/NMDA-induced excitotoxicity, an experimental model of Huntington’s disease (HD), SST positive interneuron coexpressing NPY/NADPH-d/bNOS are selectively spared whereas, projection neurons expressing NMDA receptors and DARPP- 32 are vulnerable. SST plays neuroprotective role in excitotoxicity, however, which SSTR subtypes mediate the neuroprotective role is not known. Accordingly, as a first step, we describe the colocaliztion of SSTR subtypes with DARPP-32 to determine the percentage of receptor subtypes in projection neurons. We further extended our study and compared HD transgenic mice (R6/2) with SSTR1 and 5 double knock out mice. In both strains we compared the expression pattern of NMDARs, DARPP-32, SST, bNOS and SSTRs and key downstream signaling pathways linked to the neuronal loss in HD such as PI3K, ERK1/2 PKC-α, synapsin-IIa, enkephalin and calpain. Our data shows that SSTR1/5 double knock out mice mimic the neurochemical changes of HD transgenic mice indicating a key neuroprotective role of SSTR1 and 5 in HD. To derive direct physiological implications and mechanistic explanations for the role of SSTR subtypes in excitotoxicity we used striatal brain slices and determined the effect of SSTR1 and 5 agonist, alone or in combination with NMDA on key proteins such as DARPP-32, calpain, PSD-95 and signaling pathways associated with NMDA induced neurotoxicity. Our results here show significant decrease in NMDA currents and dissociation of NMDARs heterodimerization upon treatment with SSTR1 and 5-specific agonist. Our data further demonstrates significant decrease in NMDARs expression and upregulation of SSTR1 and 5 upon agonist treatment. Unlike NMDA, activation of SSTR1 or 5 in striatal slices induced DARPP-32 phosphorylation at Thr34 and Thr75 enhanced CREB phosphorylation and inhibits expression of calpain and PSD-95. The data presented in this thesis provides a new insight for the role of SSTR subtypes in excitotoxicity with relevance to neurological disorders.

Text

2013-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42063

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/