Decreased Glutamic Acid Decarboxylase(67) MRNA Expression in Multiple Brain Areas of Patients with Schizophrenia and Mood Disorders

Reduced levels of glutamic acid decarboxylase(67) (GAD(67)), an essential enzyme for GABA synthesis, is one of the most consistent gene expression changes found in the frontal cortex of patients with schizophrenia. Recently this reduction has been shown to extend to other areas including primary sensory, primary motor and anterior cingulate (ACC) cortices. To determine the extent to which additional cortical and subcortical regions may be affected in schizophrenia, we measured the level of GAD(67) mRNA in previously unexplored areas including the orbitofrontal (OFC) and superior temporal (STG) cortices as well as the caudate, putamen, nucleus accumbens, medial dorsal thalamus and anterior thalamus using in situ hybridization. We also examined GAD(67) mRNA levels in all these regions in individuals with bipolar disorder and major depression. ANCOVA comparing GAD(67) mRNA levels in all four diagnostic groups revealed a significant reduction (approximately 30%) in layers III and IV of the OFC of patients with schizophrenia and bipolar disorder. A priori t-tests comparing GAD(67) mRNA levels between the schizophrenia and control groups revealed significant reductions in the ACC, STG, striatum and thalamus. These findings suggest that there may be a widespread reduction in GABA neurotransmission due to a decrease in the synthesis of GAD(67) in subjects with psychiatric disorders. The resulting decrease in inhibitory tone across multiple brain areas may contribute to the psychotic behavior observed in patients with schizophrenia and bipolar disorder.