D-Serine and the Pathophysiology of Schizophrenia

Abstract

Schizophrenia is a chronic, disabling psychiatric disorder characterized by psychosis, cognitive impairments, and negative symptoms such as social withdrawal and anhedonia. Pathologic changes in the brain include cortical atrophy, loss of pyramidal cell dendritic complexity and spine density, ventricular enlargement, and reduction in intracellular mediators of neuronal plasticity. Acute blockade of N-methyl-d-aspartate receptors (NMDARs) with ketamine reproduces the full range of symptoms of schizophrenia in normal volunteers. A recent genome-wide association study revealed that many of the risk genes for schizophrenia interact directly with the NMDAR such as serine racemase (SR), which synthesizes its co-agonist, d-serine, or downstream mediators of NMDAR activity. Consistent with the genetic findings, alterations in the levels of SR, d-serine, and d-amino acid oxidase have been found in schizophrenia. Genetically silencing the SR gene (SR−/−) in mice causes an 85 % reduction of d-serine in the brain and reproduces the synaptic neuropathology of schizophrenia as well as the cognitive deficits and anhedonia. Treatment of adult SR−/− mice with d-serine to restore brain levels reverses most of the neuropathology and the cognitive deficits. Placebo-controlled clinical trials in schizophrenic patients on antipsychotic drugs with d-serine or agents that act at its site on the NMDAR have shown significant reductions in symptoms including psychosis. These findings support the hypothesis that drugs that enhance NMDAR function might be effective treatments for schizophrenia, especially the cognitive and negative symptoms, which are unaffected by current treatments.