EZH2 is involved in vulnerability to neuroinflammation and depression-like behaviors induced by chronic stress in different aged mice

Abstract

Background: Microglial activation and pro-inflammatory cytokines expression is closely related to pathogenesis of depression. Aging is a known risk factor for neuroinflammation in the central nervous system and subsequent behavioral impairment. Enhancer of zeste homolog 2 (EZH2), a methyltransferase of histone H3 lysine 27 which regulates microglial activation, plays a crucial role in proinflammatory cytokines expression. However, whether the EZH2 is involved in susceptibility to depression in different ages remains elusive.

Methods: Young and aged C57BL/6 mice were exposed to chronic unpredictable mild stress for three weeks. Depression- and anxiety-like behaviors, spatial memory impairment, and the expression of pro-inflammatory cytokines, P-p65, EZH2, H3K27me3 and SOCS3 in the prefrontal cortex and hippocampus were measured using an established behavioral battery, ELISA, immunohistochemistry and western blotting techniques. Moreover, EPZ-6438, an inhibitor of EZH2, was utilized to detect the role of EZH2 in neuroinflammation and behavioral abnormalities.

Results: CUMS induced depression-like behaviors and spatial memory impairment, elevated levels of proinflammatory cytokines and P-p65, enhanced M1 microglia activation, and increased levels of EZH2, H3K27me3 and SOCS3 in the prefrontal cortex and hippocampus in young and aged mice. Both unstressed and stressed aged mice displayed attention-deficit behavioral outcomes, alteration of protein levels compared with young mice. However, inhibition of EZH2 could relieve most of behavioral and molecular alterations.

Limitations: A relative small sample size is a limitation.

Conclusions: EZH2 might be involved in susceptibility to neuroinflammation and depression-like behaviors in different aged mice.

Keywords: Aging; CUMS; Cytokines; Depresion; EZH2; Microglia.