Aging-Dependent Downregulation of SUV39H1 Histone Methyltransferase Increases Susceptibility to Stress-Induced Depressive Behavior.

Jung-Eun Lee,So-Young Park,Pyung-Lim Han

doi:10.1007/s12035-021-02529-0

Abstract

Aging induces cellular and molecular changes including gene expression alteration in the brain, which might be associated with aging-induced decrease in stress coping ability. In the present study, we investigate how aging changes the ability to cope with stress and increases sensitivity to stress. Aged mice show 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 resulting changes in SUV39H1-regulated signaling pathways in the hippocampus.

Highlights

Stress responses proceed with a neuroendocrine reaction, resulting in the release of glucocorticoids (GC) into the blood
These results suggest that the aging-dependent reduction in the expression of SUV39H1 is closely related to the aginginduced increase in the expression of Mitogen-activated protein kinase phosphatase-1 (Mkp-1)
Chromatin immunoprecipitation (ChIP) analysis indicated that the level of SUV39H1 bound to the promoter region of the Mkp-1 was significantly reduced in the hippocampus of aged mice (18 months or 18 M) compared to that of young mice (2 M) (Fig. 1e,f)

Summary

Introduction

Stress responses proceed with a neuroendocrine reaction, resulting in the release of glucocorticoids (GC) into the blood. When the stress response is activated excessively, it may cause maladaptive changes including structural and functional changes in various brain regions such as the hippocampus, prefrontal cortex, and amygdala [4, 5, 6, 7]. Brain aging advances with cellular and molecular changes including accumulation of oxidative stress, increased mitochondrial dysfunction, reduced expression of neurotrophic factors, and impaired cellular stress responses [9, 12]. These aging-related changes in the brain are likely to be associated with GCinduced events. The detailed mechanisms by which aging and stress-induced changes accumulate maladaptive changes in the brain and promote depressive behaviors are not clearly understood

Methods

Results

Conclusion