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The NMDA receptor (NMDAR) hypofunction hypothesis in schizophrenia posits that reduced NMDAR function leads to behavioral abnormalities observed in schizophrenia. Lower expression of GluN2C subunit of NMDAR has been reported in the cortex and thalamus in postmortem brains from schizophrenic patients, however its functional implications remain unknown. In the present study, we used two GluN2C KO mouse model to further characterize the deficits associated with a reduction in GluN2C, as well as to elucidate the expression pattern of the GluN2C subunit. We found cellular and synaptic deficits in GluN2C knockout mice including lower parvalbumin labeling and lower dendritic spine density, features similar to those observed in human condition. GluN2C heterozygous and knockout mice also exhibit behavioral and cognitive deficits relevant to schizophrenia. Moreover, a GluN2C/GluN2D potentiator, CIQ, attenuated NMDAR channel blocker-induced hyperlocomotion, working memory deficit as well as prepulse inhibition deficit in wildtype and heterozygous mice but not in GluN2C knockout mice. These results demonstrate that deficit in GluN2C-containing NMDARs leads to schizophrenia-like phenotypes, and establish that pharmacologic enhancement of GluN2C-containing NMDARs may lead to beneficial effects for behavioral and cognitive deficits in schizophrenia. Advisors/Committee Members: Dravid, Shashank, M., Ravikrishnan, Aparna.