Postmortem gene expression profiles in the habenulae of suicides: Implication of endothelial dysfunction in the neurovascular system

The habenula (Hb) is an epithalamic structure that links multiple forebrain areas with the mid/hindbrain monoaminergic systems. As an anti-reward center, it has been implicated in the etiology of various neuropsychiatric disorders, particularly those associated with dysregulated reward circuitry. In this regard, Hb has been proposed as a therapeutic target for treatment-resistant depression associated with a higher risk of suicide. Therefore, we aimed to gain insight into the molecular signatures of the Hb in association with suicide in individuals with major depression. Postmortem gene expression analysis identified 251 differentially expressed genes (DEGs) in the Hb tissue of suicides in comparison with Hb tissues from neurotypical individuals. Subsequent bioinformatic analyses using single-cell data from the mouse Hb showed that the levels of a subset of endothelial cell-enriched genes encoding cell-cell junctional complex and plasma membrane-associated proteins, as well as the levels of their putative upstream transcriptional regulators, were significantly affected in suicides. Taken together, the present study suggests a potential association of endothelial dysfunction in the Hb with depression and suicidal behavior. although our findings are based on a limited sample of individuals. For this study, we obtained Hb tissues from 10 suicide subjects diagnosed with major depression and 10 control subjects. All subjects were male Caucasians, and groups (suicides and controls) were matched for age, pH, and postmortem interval (PMI). Using RNAs longer than approximately 200 nucleotides from habenula tissue, GeneChip Human Gene 2.0 ST arrays was done, and anlayzed for altered gene expression in suicides.