CLSTN1 Overexpressing In Dendate Gyrus Rescues Hippocampus-dependent Memory Deficits In Fragile X Syndrome Mice

Objective:The present study is to explore the role of calsyntenin-1?Clstn1?in hippocampal-dependent memory deficits in FXS mouse model,and effects of overexpression of CLSTN1 in dentate gyrus of hippocampus on the structure of dendritic spines,synaptic connectivity and synaptic plasticity in Fmr1 KO mice.Methods:Fmr1 knockout mice?KO?(FVB.129P2-Pde6b⁺Tyr^c-ch-ch Fmr1 ^tm1Cgr/J)and wild mice(FVB.129P2-Pde6b⁺Tyr^c-ch/AntJ)were used as the animal model of FXS.Firstly,the abnormal expression of CLSTN1 protein was observed by Western blotting in Fmr1 knockout mice.Secondly,the expression of CLSTN1 was interfered by viral vectors in the dentate gyrus of the hippocampus of normal mice,which to detect the spatial memory,fear memory and social memory of mice,as well as their anxiety and motor level.And then the expression of CLSTN1 was overexpressed by viral vectors in the dentate gyrus of the hippocampus of Fmr1 knockout mice,which to detect the spatial memory,fear memory and social memory of mice,as well as their anxiety and motor level.After that,using virus-mediated fine morphological markers of neurons,the effect of overexpressing CLSTN1 in dentate gyrus of hippocampus on dendritic spines of granular cells in Fmr1 knockout mice was detected.Furthermore,using pseudorabies virus labeled neural network tracing technique,we observed whether overexpression of CLSTN1 in dentate gyrus of hippocampus of Fmr1 knockout mice could increase the strength of synaptic connections of neurons.Finally,using in vitro electrophysiological recording technique,the effect of overexpressing CLSTN1 in dentate gyrus of hippocampus on LTD in hippocampus of Fmr1 knockout mice was detected.Results:?1?CLSTN1 protein expression level is downregulated in two-month Fmr1KO mice;?2?The interference of CLSTN1 expression in the hippocampal dentate gyrus could reduce spatial memory,fear memory,and social memory in wild-type mice,but did not affect their anxiety and motor level;?3?In contrast,overexpression of CLSTN1in dentate gyrus could improve spatial memory,fear memory and social memory in Fmr1 knockout mice,but did not affect their anxiety and motor level;?4?The overexpression of CLSTN1 in the dentate gyrus of Fmr1 knockout mice increased the stability of dendritic spines of granular cells;?5?CLSTN1 overexpressing in dentate gyrus increased the intensity of Lent?DG neural circuit connection in Fmr1 KO mice.;?6?LTD in dentate gyrus of hippocampus was rescued by overexpressing CLSTN1 in Fmr1 KO mice.Conclusion:Our results suggest that CLSTN1 is closely related to hippocampal-dependent memory deficits in FXS animals.Overexpression of CLSTN1in dentate gyrus of hippocampus can repair hippocampus-dependent memory deficit in FXS mice.The results may provide new ideas for the treatment of hippocampal-dependent memory disorders in fragile X syndrome.