Aging-dependent downregulation of SUV39H1 histone methyltransferase increases susceptibility to stress-induced depressive behavior

Abstract Aging induces cellular and molecular changes including gene expression alteration in the brain, which might be associated with aging-dependent increase in vulnerability to stress-induced depression. However, the underlying mechanism is not clearly understood. In the present study, we investigate how aging changes the ability to cope with stress and increases sensitivity to stress. Aged mice have decreased expression of SUV39H1 histone methyltransferase and increased expression of Mkp-1 in the hippocampus. The siRNA-mediated knockdown of SUV39H1 increases Mkp-1 expression and suppresses p-CREB and Bdnf expression in HT22 cells and in the hippocampus of mice. Chromatin immunoprecipitation assays indicate that the levels of SUV39H1 and methylated histone-H3 bound to the promoter of the Mkp-1 in the hippocampus are reduced in aged mice. Aged mice exhibit depression-like behavior following weak stress that does not induce depressive behavior in young mice. Rosmarinic acid, a phenolic compound that increases SUV39H1 expression, reverses stress-induced changes of SUV39H1, Mkp-1, and Bdnf expression in the hippocampus via an overlapping but distinct mechanism from those of fluoxetine and imipramine and produces anti-depressive effects. These results suggest that aging increases susceptibility to stress via downregulation of SUV39H1 and changes in SUV39H1-regulated signaling pathways in the hippocampus.