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Stephan Heckers, MD; David Stone, PhD; John Walsh, MA; John Shick; Pamposh Koul; Francine M. Benes, MD, PhD

Arch Gen Psychiatry. 2002;59:521-529.

Background  Expression of messenger RNA (mRNA) for the -aminobutyric acid (GABA)–synthesizing enzyme, glutamic acid decarboxylase (GAD), in the prefrontal cortex and the number of GABAergic neurons in the hippocampus are reduced in schizophrenia and bipolar disorder. We tested the hypothesis that the expression of the 2 isoforms, one 65 kd (GAD₆₅) and the other 67 kd (GAD₆₇), is differentially affected in the hippocampus in schizophrenia and bipolar disorder.

Methods  Hippocampal sections from 15 subjects in 3 groups (control subjects and subjects with schizophrenia and bipolar disorder) were studied using an in situ hybridization protocol with sulfur 35–labeled complementary riboprobes for GAD₆₅ and GAD₆₇ mRNA. Emulsion-dipped slides were analyzed for the density of GAD mRNA–positive neurons in 4 sectors of the hippocampus and for the cellular expression level of both GAD mRNAs.

Results  The density of GAD₆₅ and GAD₆₇ mRNA–positive neurons was decreased by 45% and 43%, respectively, in subjects with bipolar disorder, but only 14% and 4%, respectively, in subjects with schizophrenia. The decreased density of GAD₆₅ mRNA–positive neurons in subjects with bipolar disorder was significant in sectors CA2/3 and dentate gyrus, and that of GAD₆₇ mRNA–positive neurons was significant in CA4, but not other hippocampal sectors. Cellular GAD₆₅ mRNA expression was significantly decreased in subjects with bipolar disorder, particularly in CA4, but not in schizophrenic subjects. Cellular GAD₆₇ mRNA expression was normal in both groups.

Conclusion  We have found a region-specific deficit of GAD₆₅ and GAD₆₇ mRNA expression in bipolar disorder.

From the Laboratory of Structural Neuroscience, McLean Hospital, Belmont, Mass (Drs Heckers, Stone, and Benes; Messrs Walsh and Shick; and Ms Koul), and Department of Psychiatry (Drs Heckers and Benes) and Program of Neuroscience (Dr Benes), Harvard Medical School, Boston, Mass.

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