Project Summary

Joseph Coyle, M.D. (Distinguished Investigator 2004) of Harvard University, notes that evidence suggests that hypofunction of a subpopulation of NMDA receptors may contribute to the symptomatic manifestations of schizophrenia. The NMDA receptor has the peculiar feature of requiring two ligands to bind to function: the glycine modulatory site (GMS) which must be occupied for glutamate to open the ion channel. Endogenous agonists at the GMS are glycine and D-serine (which is inactivated by D-amino acid oxidase (DAAO). The possible involvement of D-serine in NMDA receptor hypofunction provides a possible link to schizophrenia. Two prior research trials with D-serine resulted in significant reductions in negative symptoms, cognitive impairment and positive symptoms, and illustrates the more favorable profile for D-serine than glycine, and may be a result of greater potency at the GMS, greater penetration of the blood brain barrier, and low DAAO expression in the corticolimbic region as compared to the glycine transporter (GlyT1). Using a mouse model, Dr. Coyle will characterize these mutants by examining the effect of suppression and over-expression of Serine Racemase (SR), which synthesizes D-serine in astrocytes from L-serine, in adulthood on synaptic chemistry (particularly markers of glutamatergic neurotransmission in the cortex/hippocampus), electrophysiology of the Schaffer collateral neurotransmission in hippocampal CA1 and spontaneous behaviors and memory.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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