SPECIFIC AIMS: The administration of glutamatergic NMDA receptor (NMDAR) antagonists to human subjects elicits core

The administration of glutamatergic NMDA receptor (NMDAR) antagonists to human subjects elicits core symptoms of schizophrenia, implicating hypofunction of NMDARs in the disease process. However, identifying sensitive periods and potential cell-types of NMDAR hypofunction has proven elusive. The first strong evidence that NMDAR hypofunction occurs in cortical GABAergic interneurons during postnatal development was provided by our transgenic mice that lacked an indispensable subunit, NR1(Grin1), of NMDARs in cortical and hippocampal parvalbumin (PV)-positive interneurons (Belforte et al, 2010). The mutant mice displayed several schizophrenic-like phenotypes, including deficits of prepulse inhibition (PPI) and spatial working memory (cognitive-like symptoms), exacerbated amphetamine-induced dopamine release in ventral striatum (positivelike symptoms), and impaired evoked-gamma band local field potential (LFP) oscillation in the cortex. Interestingly, NR1 deletion in the same GABA neurons failed to produce such phenotypes when the deletion was introduced after adolescence, suggesting existence of a ‘sensitive period’ for NMDAR hypofunction. Thus, it appears that the dysregulation of GABAergic neurons is not solely attributable to NR1 deletion. Rather, the NR1 deletion may impair the postnatal maturation of GABAergic neurons and, in the absence of proper GABAergic inhibition, the refinement of cortical circuitry may be impeded. However, a more rigorous measure of spatial (cell-types) and temporal windows of NMDAR hypofunction remains to be determined. Further, the cellular and neuronal events downstream from NMDAR hypofunction during the sensitive period responsible for the elaboration of schizophrenia pathophysiology need to be delineated.