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Tsung-Ung W. Woo, MD, PhD; John P. Walsh, MS; Francine M. Benes, MD, PhD

Arch Gen Psychiatry. 2004;61:649-657.

Background  Disturbances of -aminobutyric acid interneurons in the cerebral cortex contribute to the pathophysiology of schizophrenia and bipolar disorder. The activity of these neurons is, in turn, modulated by glutamatergic inputs furnished by pyramidal neurons.

Objective  To test the hypothesis that glutamatergic inputs onto -aminobutyric acid interneurons via the N-methyl-D-aspartate (NMDA) receptor are altered in the anterior cingulate cortex in schizophrenia and bipolar disorder.

Design  A double in situ hybridization technique was used to simultaneously label the messenger RNA (mRNA) for the NMDA NR_2A subunit with ³⁵sulfur and the mRNA for the 67-kDa isoform of the -aminobutyric acid synthesizing enzyme glutamic acid decarboxylase (GAD₆₇) with digoxigenin.

Setting  Postmortem human brain studies.

Participants  We studied 17 subjects with schizophrenia, 17 subjects with bipolar disorder, and 17 normal control subjects.

Results  The density of all GAD₆₇ mRNA–containing neurons was decreased by 53% and 28%, in layers 2 and 5, respectively, in subjects with schizophrenia, whereas in subjects with bipolar disorder there was a 35% reduction in layer 2 only. For GAD₆₇ mRNA–containing neurons that co-expressed NR_2AmRNA, their numerical density was decreased by 73% and 52%, in layers 2 and 5, respectively, in subjects with schizophrenia and by 60% in layer 2 in those with bipolar disorder. In the schizophrenia group, the density of the GAD₆₇mRNA–containing neurons that did not co-express NR_2AmRNA was also decreased by 42% in layer 2. In both disease groups, the expression level of NR_2AmRNA in GAD₆₇ mRNA–containing cells was unaltered.

Conclusions  The density of -aminobutyric acid interneurons that express the NMDA NR_2Asubunit appears to be decreased in schizophrenia and bipolar disorder. Future studies will address whether subpopulations of these neurons may be differentially affected in the 2 conditions.

From the Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, Mass (Drs Woo and Benes and Mr Walsh); the Department of Psychiatry (Drs Woo and Benes) and the Program in Neuroscience (Dr Benes), Harvard Medical School, Boston, Mass; and the Massachusetts Mental Health Center, Boston (Dr Woo).