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

Abstract

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.

Keywords: Antipsychotic; Gender; Postmortem brain; Receptor; mRNA; γ-Aminobutyric acid.

Figure 1. Differential GABAergic gene expression occurs in the ACC of males and females with schizophrenia

The relative expression of each GABA-A receptor subunit and GAD67 is compared in schizophrenia and control subjects. (A) Male schizophrenia subjects have a generalized decrease in the expression of almost every gene tested relative to male controls. (B) Female schizophrenia subjects appear to have a generalized increase in the expression in almost every GABAergic gene tested. Post-hoc analyses reveal significant alterations in the expression levels of specific genes, and are summarized in the graphs. Values shown are mean ± SEM of the relative expression of each target gene normalized to the geometric mean of three housekeeping genes (GUSB, PPIA, and GAPDH), measured by qPCR. * indicates p≤0.05; ** indicates p≤0.01.

Figure 2. Medication appears to ‘correct’ GABAergic deficits in the ACC in male patients with schizophrenia

The relative expression of each GABA-A receptor subunit and GAD67 is compared in schizophrenia subjects on and off medication at the time of death. Male schizophrenia subjects on medication have a generalized increase in the expression of the majority of genes tested relative to the patients off medication. Post-hoc analyses reveal significant alterations in the expression levels of specific genes; the off medication group had significantly lower expression compared with both the controls and the on medication groups for the genes encoding GABA-Aα1 (p=0.005 and 0.006 respectively), GABA-Aα2 (p=0.010 and 0.005), GABA-Aα3 (p=0.003 and 0.007), GABA-Aγ2 (p=0.004 and 0.008), and GAD67 (p=0.005 and 0.013); expression in the control group was higher than both the on and off medication schizophrenia groups for GABA-Aα5 (p=0.012 for both) and GABA-Aβ1 (p=0.023 and 0.024 respectively), medicated schizophrenia cases showed higher expression of GABA-Aβ2 than the off medication group (p=0.015), the control group had higher expression of GABA-Aγ3 (p=0.050) and GABA-Aε (p=0.049) than the medicated schizophrenia group, and there were no changes of expression for GABA-Aδ and GABA-Aγ1. Values shown are mean + SEM of the expression of each target gene normalized to the geometric mean of three housekeeping genes (GUSB, PPIA, and GAPDH), measured by qPCR. * indicates p≤0.05; ** indicates p≤0.01.