Repression of Astrocytic Connexins in Cortical and Subcortical Brain Regions and Prefrontal Enrichment of H3K9me3 in Depression and Suicide

Background: Major depressive disorder has been associated with dysfunctional astrocytic networks. The underlying causes, extent, and consequences of such dysfunctions remain to be characterized. Astrocyte-astrocyte communication occurs principally through gap junction channels primarily formed by connexin 30 and 43 (CX30 and CX43). We previously reported decreased connexin expression in the prefrontal cortex of depressed suicides. In the present study, we investigated whether these changes are mediated by epigenetic regulation, and expanded gene expression quantifications to other cortical and subcortical regions to assess the regional distribution of connexion disruptions in depressed suicides. Methods: The expression of CX30 and CX43 was measured by real-time PCR in samples of neocortex (Brodmann areas 4 and 17), cerebellar cortex, mediodorsal thalamus, and caudate nucleus of 22 depressed suicides and 22 matched sudden-death controls. Chromatin immunoprecipitation was used to measure enrichment levels of the repressive chromatin mark H3K9me3 in the prefrontal cortex. Results: We found a consistent downregulation of connexin genes in all regions examined, except in the cerebellum where an increase in the expression of CX30 was measured and using chromatin immunoprecipitation we observed an enrichment of H3K9me3 for both Cx30 and Cx43 in the prefrontal cortex. Conclusions: Our study shows widespread astrocytic CX gene repression in depressed suicides that is mediated, at least in part, through epigenetic mechanisms. Taken together, these findings support the notion of widespread cerebral astrocytic dysfunction in major depressive disorder.