Chd8 Rescued TB1-induced Neurological Deficits By Suppressing Apoptosis And Autophagy Via Wnt Signaling Pathway

Background:Traumatic brain injury(TBI)and autism spectrum disorder(ASDs)share several same biochemical mechanisms,and the similar symptoms such as learning memory impairments and cognitive dysfunction.Chromodomain helicase DNA binding protein 8(CHD8),a member of the CHD family of ATP-dependent chromatin-remodeling factors,is one of the top risk genetic factors in ASDs and involved in Wnt/?-catenin signaling.However,the possible effects of Chd8 on experimental TBI remain poorly understood.The main task of this study is to test the effects of chd8 on neuroprotective function and cognitive recovery post TBI.Methods:Double Immunofluorescent Staining were employed to determine whether chd8 co-localized with neurons in adult mice.Western Blot Analysis and RT-qPCR were used to detect the expression pattern of chd8 and ?-catenin and the effects of chd8 on wnt,apoptosis and autophagy following TBI.Additionally,the spatial cognitive abilities were evaluated by Morris water maze(MWM).Result:In vivo,we found that chd8 co-localized with neurons in the prefrontal cortex,hippocampus and cortex,and it predominantly presented in the nucleus of the neurons.Both chd8 and ?-catenin expression peaked at 12 h and shared the similar change-tendency after TBI.Using Chd8-siRNA,Chd8 knockdown inhibited wnt pathway,promoted the activation of apoptosis and autophagy,also caused learning and memory impairments both at normal and TBI conditions.Whereas,overexpression of chd8 enhanced wnt signaling pathway,suppressed apoptosis and autophagy activation after TBI.In vitro,a significant increase of chd8 and ?-catenin expression was observed in HT22 cells after lipopolysaccharide(lps)treatment and mechanical injury,respectively.Chd8-siRNA inhibited wnt signaling pathway,increased apoptosis and autophagy activation in lps-stimulated HT22 cells.But activation of wnt signaling inverted the above effects of chd8-siRNA.Conclusion:Our results demonstrate that chd8 exerts neuroprotection and cognitive recovery through inhibiting apoptosis and autophagy activation following TBI,at least in part by wnt signaling pathway.