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Journal of Neuroscience, Vol 16, 19-30, Copyright © 1996 by Society for Neuroscience
Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics
S Akbarian, NJ Sucher, D Bradley, A Tafazzoli, D Trinh, WP Hetrick, SG Potkin, CA Sandman, WE Bunney Jr and EG Jones
Department of Anatomy and Neurobiology, University of California, Irvine 92717, USA.
NMDA receptor antagonists can induce a schizophrenia-like psychosis, but
the role of NMDA receptors in the pathophysiology of schizophrenia remains
unclear. Expression patterns of mRNAs for five NMDA receptor subunits
(NR1/NR2A-D) were determined by in situ hybridization in prefrontal,
parieto-temporal, and cerebellar cortex of brains from schizophrenics and
from neuroleptic-treated and nonmedicated controls. In the cerebral cortex
of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D
subunits were preferentially expressed in layers II/III, Va, and VIa, with
much higher levels in the prefrontal than in the parieto-temporal cortex.
Levels of mRNA for the NR2C subunit were very low overall. By contrast, the
cerebellar cortex of both schizophrenics and controls contained very high
levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs
were very low, except NR1, for which levels were moderate. Significant
alterations in the schizophrenic cohort were confined to the prefrontal
cortex. Here there was a shift in the relative proportions of mRNAs for the
NR2 subunit family, with a 53% relative increase in expression of the NR2D
subunit mRNA. No comparable changes were found in neuroleptic-treated or
untreated controls. These findings indicate regional heterogeneity of NMDA
receptor subunit expression in human cerebral and cerebellar cortex. In
schizophrenics, the alterations in expression of NR2 subunit mRNA in
prefrontal cortex are potential indicators of deficits in NMDA
receptor-mediated neurotransmission accompanying functional hypoactivity of
the frontal lobes.
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