In subjects with
schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in
gamma-aminobutyric acid (
GABA)-mediated inhibitory circuitry. To test the hypothesis that altered
GABA-mediated circuitry in the DLPFC of subjects with
schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of
GABA neurotransmission, we conducted a systematic expression analysis of
GABA-related transcripts in the DLPFC of 14 pairs of
schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized
DNA microarray with enhanced sensitivity and specificity. Subjects with
schizophrenia exhibited expression deficits in
GABA-related transcripts encoding (1) presynaptic regulators of
GABA neurotransmission (67 kDa
isoform of
glutamic acid decarboxylase (GAD(67)) and
GABA transporter 1), (2)
neuropeptides (
somatostatin (SST),
neuropeptide Y (NPY) and
cholecystokinin (CCK)) and (3)
GABA(A) receptor subunits (alpha1, alpha4, beta3, gamma2 and delta). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD(67), SST and alpha1 subunit
mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to
antipsychotic medications. These findings suggest that
schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain
GABA(A) receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in
schizophrenia is mediated by altered
GABA neurotransmission in certain DLPFC microcircuits.