Sex differences in GABAergic gene expression occur in the anterior cingulate cortex in schizophrenia

GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n=21) and a comparison group of individuals without a history of psychiatric illness (n=18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Aε. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression of GABA-Aα1-3, GABA-Aβ2, GABA-Aγ2, and GAD67 in the medicated group compared to the unmedicated group. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication.