Sex Differences in the Expression of the α5 Subunit of the GABAA 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(A)alpha 5 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(A)alpha 5 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(A)alpha 5 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(A) receptor isoform that is brought about by alcohol exposure.