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We have used mutant mice to probe the roles of the endogenous co-agonists of the NMDA receptor (NMDAR), D -serine and glycine, in fear learning and memory. Serine racemase knockout (SR−/−) mice have less than 15% of wild type forebrain levels of D -serine, whereas glycine transporter 1 heterozygous knockout (GlyT1+/−) mice have elevated synaptic glycine. While cued fear was normal in both delay and trace conditioned mice of both mutant genotypes, contextual fear was affected in trace conditioned subjects: SR−/− mice showed decreased contextual freezing, whereas GlyT1+/− mice showed elevated contextual freezing. These results indicate that endogenous co-agonists of the NMDAR modulate the conditioning of contextual fear responses, particularly in trace conditioning. They further suggest that endogenous glycine can compensate for the D -serine deficiency in cued and contextual fear following delay conditioning. [ABSTRACT FROM AUTHOR]

Abstract: Reduction in cortical presynaptic markers, notably parvalbumin (PV), for the chandelier subtype of inhibitory γ-amino-butyric acid (GABA) interneurons is a highly replicated post-mortem finding in schizophrenia. Evidence from genetic and pharmacological studies implicates hypofunction of N-methyl-d-aspartate receptor (NMDAR)-mediated glutamatergic signaling as a critical component of the pathophysiology of schizophrenia. Serine racemase (SR) produces the endogenous NMDAR co-agonist d-serine, and disruption of the SR gene results in reduced NMDAR signaling. SR null mutant (−/−) mice were used to study the link between NMDAR hypofunction and decreased PV expression, assessed by immunoreactive (IR) cell density in the medial prefrontal cortex and hippocampus and protein levels in brain homogenates from the frontal cortex and hippocampus. Contrary to expectations, SR −/− mice showed modest elevations in PV–IR cell density and no difference in PV expression in brain homogenate. To control for these surprising results, we investigated PV expression in mice and rats following subchronic phencyclidine or ketamine treatments in adulthood. PV expression was not affected by drug these treatment in either species, failing to reproduce previously published findings. Our findings challenge the hypothesis that pathological deficits in PV expression are simply a consequence of NMDAR hypofunction. [ABSTRACT FROM AUTHOR]