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Decreased Glutamic Acid Decarboxylase₆₇ Messenger RNA Expression in a Subset of Prefrontal Cortical -Aminobutyric Acid Neurons in Subjects With Schizophrenia

David W. Volk, MS; Mark C. Austin, PhD; Joseph N. Pierri, MS, MD; Allan R. Sampson, PhD; David A. Lewis, MD

Arch Gen Psychiatry. 2000;57:237-245.

Background  Markers of -aminobutyric acid (GABA) neurotransmission seem to be altered in the prefrontal cortex (PFC) of subjects with schizophrenia. We sought to determine whether the expression of the messenger RNA (mRNA) for the synthesizing enzyme of GABA, glutamic acid decarboxylase₆₇ (GAD₆₇), is decreased in the PFC of subjects with schizophrenia, whether this change is present in all or only some GABA neurons, and whether long-term treatment with haloperidol decanoate contributes to altered GAD₆₇ mRNA expression.

Methods  Tissue sections from 10 pairs of subjects with schizophrenia and control subjects and 4 pairs of haloperidol-treated and control monkeys were processed for in situ hybridization histochemical analysis with sulfur-35–labeled oligonucleotide probes for GAD₆₇ mRNA and exposed to nuclear emulsion. Within each layer of PFC area 9, neurons expressing a detectable level of GAD₆₇ mRNA were quantified for cell density and the relative level of mRNA expression per cell (grain density per neuron).

Results  In subjects with schizophrenia, the density of labeled neurons was significantly (P<.05) decreased by 25% to 35% in cortical layers 3 to 5. In contrast, the mean grain density per labeled neuron did not differ across subject groups. Similar analyses in monkeys revealed no effect of long-term haloperidol treatment on either the density of the labeled neurons or the grain density per labeled neuron.

Conclusions  These findings indicate that in subjects with schizophrenia, GAD₆₇ mRNA expression is relatively unaltered in most PFC GABA neurons but is reduced below a detectable level in a subset of GABA neurons. Altered GABA neurotransmission in this subset may contribute to PFC dysfunction in subjects with schizophrenia.

From the Departments of Neuroscience (Mr Volk and Dr Lewis), Psychiatry (Drs Austin, Pierri, and Lewis), and Statistics (Dr Sampson), University of Pittsburgh, Pittsburgh, Pa.