PDF(Pubmed)
Abstract：
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.
摘要：
编码电压门控钠通道α亚基Nav1的SCN8A基因突变。在癫痫患者中报告了6例，智力障碍和自闭症谱系障碍的特征。SCN8A在中枢神经系统中广泛表达，包括小脑.小脑功能障碍与自闭症谱系障碍有关。我们研究了C57BL/6J品系背景下的条件Scn8a敲除小鼠，这些小鼠在小脑Purkinje细胞中特别缺乏Scn8a表达（Scn8aflox/flox，L7Cre+小鼠)。通过免疫组织化学和MR成像分析小脑形态。对小鼠进行了一系列行为测试，包括加速旋转杆，开放领域，高架加上迷宫，明暗过渡盒,三个房间，男女互动，社会嗅觉,和水T迷宫测试。使用膜片钳记录来评估Purkinje细胞中的诱发动作电位。行为表型表明，Scn8aflox/flox，L7Cre+小鼠的社交互动受损，运动学习和逆转学习，以及增加重复行为和焦虑样行为。5个月大的时候,Scn8aflox/flox，L7Cre小鼠开始表现出小脑Purkinje细胞丢失和分子厚度降低。在9个月大的时候，Scn8aflox/flox，L7Cre小鼠表现出小脑大小减小，小脑浦肯野细胞数量减少，有证据表明分子层和小脑深部核有额外的神经变性。Scn8aflox/flox中的浦肯野细胞，L7Cre+小鼠表现出减少的重复放电。一起来看,我们的实验表明，小脑浦肯野细胞中Scn8a表达的丧失会导致小脑变性和几种ASD相关行为。我们的研究证明了小脑Purkinje细胞中Scn8a丢失对ASD行为缺陷特征的特定贡献。然而,应该注意的是，我们在这里报道的观察到的效果是针对C57BL/6基因组类型的。
