Sex Differences in the Expression of the α5 Subunit of the GABA Receptor in Alcoholics with and without Cirrhosis of the Liver.

Background: Alcohol exposure alters the expression of a large number of genes, resulting in neuronal adaptions and neuronal loss, but the underlying mechanisms are largely unknown. miRNAs are gene repressors that are abundant in the brain. A recent study identified ~ 35 miRNAs that are up-regulated in the prefrontal cortex of human alcoholics and predicted to target genes that are down-regulated in the same region. Although interactions between alcohol-responsive miRNAs and their target genes have been predicted, few studies have validated these predictions.

Methods: We measured the expression of GABA α5 mRNA in the prefrontal and motor cortices of human alcoholics and matched controls using real-time PCR. The expression of miR-203 was measured in a subset of these cases. The predicted interaction of miR-203 and GABRA5 was validated for miR-203 using a luciferase reporter assay.

Results: In both frontal and motor cortices, the expression of GABA α5 was significantly lower in cirrhotic alcoholics compared with controls. Further, the pattern of expression between the groups was significantly different between males and females. The expression of miR-203 was higher in the prefrontal cortex of cirrhotic alcoholics compared with controls and uncomplicated alcoholics. These differences were particularly marked in female cases. Cotransfection of GABRA5 with miR-203 in HEK293T cells reduced luciferase reporter activity.

Conclusion: There are sex differences in the expression of GABA α5 and miR-203 in the brain of human alcoholics which are particularly marked in alcoholics with cirrhosis of the liver. Further, miR-203 may mediate the changes in expression of this GABA receptor isoform that is brought about by alcohol exposure.