This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Degeneration of the medium spiny projection neurons (MSNs) in the striatum underlies the neuropathology of Huntington?s Disease (HD). Excitotoxicity mediated by the activation of N-Methyl-D-Aspartate (NMDA) receptors may play a critical role in the selective demise of the MSNs in HD. The underlying mechanisms are unknown. Recent evidence suggests that the localization of NMDA receptors can have distinct effects on neuronal survival. In the postsynaptic densities (PSD) of glutamatergic synapses, synaptic scaffolds of the membrane-associated guanylate kinase (MAGUK) family proteins organize glutamate receptors and their associated signaling complexes important for growth, plasticity, and survival, thus may have a role in neuronal survival. A transgenic mouse strain in our laboratory lacking PSD-95, a prototypical PDZ domain-containing, NMDAR-interacting MAGUK abundant in the PSD, develops hindlimb clasping and motor deficits associated with dysregulation of NMDA receptor expression signaling. The neurological phenotypes are robust, progressive, and dominant, resembling those displayed by mouse models of striatal degeneration. These mice provide a unique in vivo system to explore the molecular and cellular mechanisms underlying MSN susceptibility. We hypothesize that PSD-95 plays an important role in the survival of striatal MSNs and their vulnerability to NMDAR excitotoxicity, and does so through regulating the functional localization and activity of striatal NMDARs and their integration into the PSD signaling complexes. We are testing this hypothesis by characterizing the striatal NMDARs, striatal neurodegeneration, and NMDAR-dependent excitotoxicity in PSD-95 deficient mice. Successful completion of the proposed experiments may enhance our understanding of the molecular mechanisms underlying stroke and Huntington's Disease.
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