Gamma-H2AX upregulation caused by Wip1 deficiency increases depression-related cellular senescence in hippocampus

Abstract

The PP2C family member Wild-type p53-induced phosphatase 1 (Wip1) critically regulates DNA damage response (DDR) under stressful situations. In the present study, we investigated whether Wip1 expression was involved in the regulation of DDR-induced and depression-related cellular senescence in mouse hippocampus. We found that Wip1 gene knockout (KO) mice showed aberrant elevation of hippocampal cellular senescence and of γ-H2AX activity, which is known as a biomarker of DDR and cellular senescence, indicating that the lack of Wip1-mediated γ-H2AX dephosphorylation facilitates cellular senescence in hippocampus. Administration of the antidepressant fluoxetine had no significant effects on the increased depression-like behaviors, enriched cellular senescence, and aberrantly upregulated hippocampal γ-H2AX activity in Wip1 KO mice. After wildtype C57BL/6 mice were exposed to the procedure of chronic unpredictable mild stress (CUMS), cellular senescence and γ-H2AX activity in hippocampus were also elevated, accompanied by the suppression of Wip1 expression in hippocampus when compared to the control group without CUMS experience. These CUMS-induced symptoms were effectively prevented following fluoxetine administration in wildtype C57BL/6 mice, with the normalization of depression-like behaviors. Our data demonstrate that Wip1-mediated γ-H2AX dephosphorylation may play an important role in the occurrence of depression-related cellular senescence.

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

“…Surprisingly, KO MEF cells proliferated at a higher rate than WT MEF cells at early passages (P1 and P2); however, the growth rate of KO MEF cells was dramatically decreased, and the cells almost ceased to proliferate at late passages (P5) (Figure 1a). Previous reports have suggested that senescent cells are larger than nonsenescent cells, are stained by senescence‐associated beta‐galactosidase (SA‐β‐gal), and showed the increased activity of γ‐H2AX, the phosphorylation form of histone H2A member X at serine 139 (Dimri et al, 1995; He et al, 2016). To evaluate the cellular senescence, we examined the size of MEF cells and performed SA‐β‐gal assays and confocal imaging of γ‐H2AX.…”

Long‐term stability and characteristics of behavioral, biochemical, and molecular markers of three different rodent models for depression

“…The UCMS model includes chronic depression by presenting unpredictable stress stimuli (Gupta et al, ) such as multiple, randomly scheduled food and water deprivation, overnight illumination, cage tilting, and other similar stressors that may be associated with human patients (Boyle et al, ). In most published studies, the UCMS model induced depression for 2–4 weeks, but some have been tested for up to eight weeks (He et al, ; Wu et al, ; Xia et al, ; Yan et al, ; N. Zhang et al, ). High levels of serum cortisol, related to elevated hypothalamo‐pituitary‐adrenal (HPA) axis activity, can be associated with depression.…”

Two Weeks of Variable Stress Increases Gamma-H2AX Levels in the Mouse Bed Nucleus of the Stria Terminalis

“…To maintain consistency with our previous research (Hare et al, 2012) and the methods of others that have investigated DSBs using a variable stress procedure (He et al, 2016), mice assigned to the 14-day variable stress condition were individually housed following the first stressor, while control animals remained group housed for the duration of the experiment. To prevent habituation, stressors were administered in a pseudorandom sequence in which all stressors were performed before any stressor was repeated.…”

“…Notably, a chronic unpredictable mild stress model increased DSBs at two weeks in the hippocampus, and produced a further increase at four weeks that was blocked by antidepressant treatment that also rescued behavioral deficits (He et al, 2016). Homotypic restraint stress exposure for 4 h per day over a two-week period increased DNA DSBs in the frontal cortex, an effect that was blocked by administration of a β2-adrenergic antagonist (Hara et al, 2013).…”

“…Neuronal activation brought about by stress may produce different outcomes as stress hormones slow DNA repair (Flint et al, 2007) and promote the accumulation of DNA damage (Hara et al, 2011). Very few studies have examined neuronal DSB levels after stress, and those that have are limited to a single time point after stress (Hara et al, 2013; He et al, 2016). These studies demonstrate an increase in γH2AX following stress; however, it remains unclear whether the increase represents damage accumulated during stress exposure or unrepaired damage generated by the final stress experience.…”