Decreased glutamic acid decarboxylase(67) messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia

Background: Markers of gamma-aminobutyric acid (GABA) neurotransmission see m to be altered in the prefrontal cortex (PFC) of subjects with schizophren ia. We sought to determine whether the expression of the messenger RNA (mRN A) for the synthesizing enzyme of GABA, glutamic acid decarboxylases(67) (G AD(67)), is decreased in the PFC of subjects with schizophrenia, whether th is change is present in all or only some GABA neurons, and whether long-ter m treatment with haloperidol decanoate contributes to altered GAD(67) mRNA expression. Methods: Tissue sections from 10 pairs of subjects with schizophrenia and c ontrol 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 GAD(67) mRNA and exposed to nuclear emul sion. Within each layer of PFC area 9, neurons expressing a detectable leve l of GAD(67) mRNA were quantified for cell density and the relative level o f 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. I n contrast, the mean grain density per labeled neuron did not differ across subject groups. Similar analyses in monkeys revealed no effect of long-ter m 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, G AD(67) mRNA expression is relatively unaltered in most PFC GABA neurons but is reduced below a detectable level in a subset of GABA neurons. Altered G ABA neurotransmission in this subset may contribute to PFC dysfunction in s ubjects with schizophrenia.