SELECTIVE ALTERATIONS IN GENE-EXPRESSION FOR NMDA RECEPTOR SUBUNITS IN PREFRONTAL CORTEX OF SCHIZOPHRENICS

NMDA receptor antagonists can induce a schizophrenia-like psychosis, b ut the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor s ubunits (NR1/NR2A-D) were determined by in situ hybridization in prefr ontal, parieto-temporal, and cerebellar cortex of brains from schizoph renics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR 2A, NR2B, and NR2D subunits were preferentially expressed in layers II /III, Va, and VIa, with much higher levels in the prefrontal than in t he parieto-temporal cortex. Levels of mRNA for the NR2C subunit were v ery low overall. By contrast, the cerebellar cortex of both schizophre nics and controls contained very high levels of NR2C subunit mRNA, whe reas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophre nic cohort were confined to the prefrontal cortex. Here there was a sh ift in the relative proportions of mRNAs for the NR2 subunit family, w ith a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated con trols. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizo phrenics, the alterations in expression of NR2 subunit mRNA in prefron tal cortex are potential indicators of deficits in NMDA receptor-media ted neurotransmission accompanying functional hypoactivity of the fron tal robes.