The involvement of the NMDA receptor d-serine/glycine site in the pathophysiology and treatment of schizophrenia

Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a d-serine/glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. This review outlines the complex regulation of endogenous NMDAR d-serine/glycine site agonists and explores their contribution to schizophrenia pathogenesis and their potential clinical utility. Genetic studies have associated genes influencing NMDAR d-serine/glycine site activation with an increased susceptibility to schizophrenia. Postmortem studies have identified abnormalities in several transcripts affecting d-serine/glycine site activity, consistent with in vivo reports of alterations in levels of endogenous d-serine/glycine site agonists and antagonists. Genetically modified mice with aberrant NMDAR d-serine/glycine site function model certain features of the negative and cognitive symptoms of schizophrenia, and similar behavioral abnormalities have been observed in other candidate genes models. Compounds that directly activate the NMDAR d-serine/glycine site or inhibit glycine transport have demonstrated beneficial effects in preclinical models and clinical trials. Future pharmacological approaches for schizophrenia treatment may involve targeting enzymes that affect d-serine synthesis and metabolism.