Structural And Functional Abnormalities In The Deep Cerebellar Nuclei Contribute To Motor Skill Learning Disability In Fragile X Syndrome Mice

Backgroud:Fragile X syndrome（FXS）is a leading form of inherited intellectual disability and single-gene cause of autism spectrum disorder（ASD）.In addition to cognitive impairment,social behavioral impairment,neurological deficits and facial abnormalities,patients may also present with motor skill learning disability.The deep cerebellar nucleus（DCN）plays an important role in the cerebrocerebellar loop that regulates motor learning.However,the relationship between motor skill learning disability and DCN in FXS remains to be investigated.Objective:This study aims to investiate whether Fmr1 KO mice are characterized by motor skill learning disability,and to explore the role of DCN in the process of motor skill learning,as well as the structural and functional status of dendritic spines of neurons in DCN.Methods:Fmrl knockout mice（KO）(FVB.129P2-Pde6b⁺Tyr^c-ch Fmr1 ^tmlCgr/J)and wild mice(FVB.129P2-Pde6b⁺Tyr^c-ch/Ant J)were used as the animal model of FXS.1)Evaluate the ability of motor skill learning by single pallet reaching task and beam walking test;2)Injecting the tool virus into DCN in WT mice,we evaluate the ability of motor skill learning;3)Using viru for single cell labeling,we detect the dendritic spine structure of neurons in DCN;4)Use fiber photometry to record the activity of neurons in DCN.Result:1)Compared with mice in the control group,Fmr1 KO mice are characterized by motor skill learning disability;2)After inhibiting the neurons in DCN,mice showed obvious impairments in motor skill learning;3)The dendritic spine structure of neurons in the medial nucleus and the interposition nucleus of Fmr1 KO mice was significantly abnormal;4)The activity of neurons in the medial nucleus and the interposition nucleus of Fmr1 KO mice was significantly weaker than that in control mice..Conclusion:The medial nucleus and the interposition nucleus in DCN of Fmr1 KO mice are abnormally developed,leading to motor skill learning defects in mice.