Phactr4 promotes oxidative stress and behavioral disorder caused by chronic stress via regulating PP1/GSK3-β pathway

Oxidative stress, defined as a process triggered by an imbalance between the accumulation of free radicals and antioxidant defences, has been considered implicated in many neurological disorders, including major depressive disorder (MDD). In the present study, we demonstrated that the expression of phosphatase and actin regulatory factor 4 (Phactr4) was increased within the dentate gyrus (DG) region of the hippocampus of the chronic stress-induced depressive mice. Phactr4 has been shown to enhance oxidative stress in the brain by interacting with protein phosphatase 1 (PP1) and synergistically reducing the level of phosphorylation of glycogen synthase kinase 3β (GSK3β), thus enhance the susceptibility to stress stimulation in mice. Knocking down phactr4 in the hippocampal DG regions can suppressed GSK3β activation, alleviate oxidative stress, and further improve the depression-like behaviors in mice. More interestingly, we further found physical exercise can downregulate the level of Phactr4, reduce the accumulation of reactive oxygen species (ROS) in the brain, ameliorate neuronal damage, and reverse depressive-like behaviors in mice. These findings suggest that physical exercise may promote the restoration of oxidative stress in brain and ameliorates depressive behaviors in mice by down-regulating the Phactr4-PP1-GSK3β pathway.