Featured Finding Figure
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 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 postmortem 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 kilodalton isoform of glutamic acid decarboxylase (GAD67) and GABA transporter 1], 2) neuropeptides [somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin CCK)], and 3) GABAA receptor subunits (α1, α4, β3, γ2, and δ). 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, GAD67, SST, and α1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications.
The figure summarizes these findings and those of previous studies. Altered GABA neurotransmission by parvalbumin (PV)-containing neurons (green) is indicated by gene expression deficits in these neurons and associated changes in their synapses, a decrease in expression of the GABA membrane transporter (GAT1) in their terminals and an upregulation of GABAA receptor α2 subunit at the axon initial segments of pyramidal neurons (lower enlarged square). Decreased expression of both SST and NPY mRNAs indicates alterations in SST and/or NPY-containing neurons (blue) that target the distal dendrites of pyramidal neurons. These changes appear to be accompanied by a downregulation of GABAA receptor subunits, including the α1 and γ2 subunits present in receptors that mediate synaptic (phasic) inhibition and the α4 and δ subunits present in receptors that mediate extrasynaptic (tonic) inhibition (upper enlarged square), in dendrites of pyramidal neurons. Decreased CCK mRNA levels indicate an alteration of CCK-containing large basket neurons (purple) that represent a separate source of perisomatic inhibition from PV-containing neurons. Gene expression in calretinin (CR)-containing GABA neurons (red) does not seem to be altered. Together, these findings suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.
Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HA, Volk DW, Mirnics K, Lewis DA: Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Molecular Psychiatry 13: 147-161, 2008.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
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