Molecular Mechanism Underlying Abnormal Social Preference Behavior In Mice Model Of Fragile X Syndrome

Objective:By exploring the molecular mechanism of abnormal social behavior in mice model of FXS,this study intended to deepen the understanding of the pathological mechanism of FXS.Acquired re-expression of FMRP in the neurons of Fmr1 KO mice by AAV mediates the reference and basis for FXS gene therapy.Methods:The social preference behavior of Fmr1 KO mice was detected by three boxes of social behavior experiments;the total protein of mouse hippocampus was extracted and Western blotting was used to detect the occurrence of APP,NMDA receptor,and its downstream proteins Akt,GSK3,Cleared caspase3,Caspase3 and Bax protein Variety.293T cells were transfected with AAV-FMRP plasmid to obtain AAV-FMRP virus vector.Stereotactic injection delivered AAV-FMRP into the lateral ventricle of Fmr1 KO mice.Immunohistochemical method was used to analyze the distribution of FMRP expression in the brain area.Immunofluorescence analysis was used.Expression and location of FMRP in brain neurons.Results:It was found that Fmr1 KO mice lacking FMRP expression had abnormal social behavior;in the hippocampus tissues of Fmr1 KO mice,the expression levels of APP and GluN2A were significantly increased,while p-Akt,p-GSK3? and pro-apoptosis-related protein Cleared The expression levels of caspase3 and Bax increased APP and GluN2A may cause Fmr1 KO mice to exhibit abnormal social behavior through the effects of Cleaved caspase3,Bax,and Akt-GSK3?,respectively.The range of FMRP expression mediated by AAV-FMRP is mainly concentrated in tissues such as hippocampus and parietal cortex.Acquired expression of FMRP can be achieved in the brain of Fmr1 KO mice.Conclusions:FMRP can regulate the social behavior of mice.In the absence of FMRP,mice have abnormal social behavior.The absence of FMRP makes APP and GluN2A mRNAs lose their translation inhibitory effect,and their expression levels increase in the hippocampus of Fmr1 KO mice.APP may induce neuronal apoptosis through Cleaved caspase3 and Bax;GluN2A may trigger the disturbance of neuronal synaptic plasticity through the effect on Akt-GSK3? signaling.APP and GluN2A may induce increased neuronal apoptosis and disturbance of dendritic plasticity,respectively,which may be a factor of abnormal social behavior in Fmr1 KO mice.AAV-FMRP-mediated acquisition of FMRP in the hippocampus and parietal cortex of Fmr1 KO mice is feasible.This method may become a gene therapy approach for FXS.