Social Deficits and Cerebellar Degeneration in Purkinje Cell Scn8a Knockout Mice

作者：Xiaofan Yang, Hongqiang Yin, Xiao‐Jing Wang, Yueqing Sun, Xianli Bian, Gaorui Zhang, Anning Li, Aihua Cao, Baomin Li, Darius Ebrahimi‐Fakhari, Zhuo Yang, Miriam H. Meisler, Qiji Liu · 发表于：Frontiers in Molecular Neuroscience · 年份：2022 · DOI：10.3389/fnmol.2022.822129 · 被引用次数：11 · 研究领域：Autism Spectrum Disorder Research、Genetics and Neurodevelopmental Disorders、RNA regulation and disease

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 mole...