Disturbances in
glutamate neurotransmission are thought to be one of the major contributing factors to the pathophysiology of
schizophrenia. In the dorsolateral prefrontal cortex (DLPFC),
glutamate neurotransmission is largely mediated by
AMPA receptors. Data regarding alterations of subunit expression in the brains of patients with
schizophrenia remain equivocal. This may be due to differences in technique sensitivity, endogenous control selection for normalization of data, or effect of
antipsychotic drug treatment in different cohorts of
schizophrenia. This study attempted to address these issues by examining the expression of
AMPA receptor subunits and splice variants in the DLPFC of two
schizophrenia cohorts using quantitative PCR (qPCR) with normalization to the geometric mean of multiple endogenous controls. In addition, a non-human primate model of chronic
antipsychotic drug administration was used to determine the extent to which the transcript expression may be altered by
antipsychotic drug treatment in the primate DLPFC.
AMPA receptor subunits and flip and/or flop splice variants were not significantly different in the DLPFC of
schizophrenia subjects versus controls in either of the two cohorts. However, in rhesus monkeys chronically treated with
antipsychotic drugs,
clozapine treatment significantly decreased GRIA1 and increased GRIA3
mRNA expression, while both
clozapine and
haloperidol increased the expression of GRIA2 subunit
mRNA. Expression of
AMPA receptor splice variants was not significantly altered by
antipsychotic drug administration. This is the first study to show that
AMPA receptor subunit mRNAs in the primate DLPFC are altered by
antipsychotic drug administration.
Antipsychotic drug-induced alterations may help explain differences in human post-mortem studies regarding
AMPA receptor subunit expression and provide some insight into the mechanism of action of
antipsychotic drugs.