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Mutations in the  SCN8A  gene encoding the voltage-gated sodium channel α-subunit Nav1. 6 have been reported in individuals with epilepsy, intellectual disability and features of autism spectrum disorder.  SCN8A  is widely expressed in the central nervous system, including the cerebellum. Cerebellar dysfunction has been implicated in autism spectrum disorder. We investigated conditional  Scn8a  knockout mice under C57BL/6J strain background that specifically lack  Scn8a  expression in cerebellar Purkinje cells ( Scn8a   flox / flox  ,  L7Cre  +  mice). Cerebellar morphology was analyzed by immunohistochemistry and MR imaging. Mice were subjected to a battery of behavioral tests including the accelerating rotarod, open field, elevated plus maze, light-dark transition box, three chambers, male-female interaction, social olfaction, and water T-maze tests. Patch clamp recordings were used to evaluate evoked action potentials in Purkinje cells. Behavioral phenotyping demonstrated that  Scn8a   flox / flox  ,  L7Cre  +  mice have impaired social interaction, motor learning and reversal learning as well as increased repetitive behavior and anxiety-like behaviors. By 5 months of age,  Scn8a   flox / flox  ,  L7Cre  +  mice began to exhibit cerebellar Purkinje cell loss and reduced molecular thickness. At 9 months of age,  Scn8a   flox / flox  ,  L7Cre  +  mice exhibited decreased cerebellar size and a reduced number of cerebellar Purkinje cells more profoundly, with evidence of additional neurodegeneration in the molecular layer and deep cerebellar nuclei. Purkinje cells in  Scn8a   flox / flox  ,  L7Cre  +  mice exhibited reduced repetitive firing. Taken together, our experiments indicated that loss of  Scn8a  expression in cerebellar Purkinje cells leads to cerebellar degeneration and several ASD-related behaviors. Our study demonstrated the specific contribution of loss of Scn8a in cerebellar Purkinje cells to behavioral deficits characteristic of ASD. However, it should be noted that our observed effects reported here are specific to the C57BL/6 genome type.

Social Deficits and Cerebellar Degeneration in Purkinje Cell Scn8a Knockout Mice