Social Deficits and Cerebellar Degeneration in Purkinje Cell Scn8a Knockout Mice.
Social Deficits and Cerebellar Degeneration in Purkinje Cell Scn8a Knockout Mice.
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浦肯野细胞 Scn8a 基因敲除小鼠的社交缺陷和小脑变性
DOI：
10.3389/fnmol.2022.822129
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发表时间：
2022
影响因子：
4.8
通讯作者：
Liu, Qiji
中科院分区：
文献类型：
--
作者：
Yang, Xiaofan;Yin, Hongqiang;Wang, Xiaojing;Sun, Yueqing;Bian, Xianli;Zhang, Gaorui;Li, Anning;Cao, Aihua;Li, Baomin;Ebrahimi-Fakhari, Darius;Yang, Zhuo;Meisler, Miriam H.;Liu, Qiji
编码电压门控钠通道α-亚基Nav1的SCN8A基因突变据报道，癫痫、智力残疾和自闭症谱系障碍患者中有6例。SCN8A广泛表达于中枢神经系统，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菌株背景下小脑浦肯野细胞特异性缺乏Scn8a表达的条件Scn8a敲除小鼠（Scn8aflox/flox， L7Cre+小鼠）。免疫组织化学和磁共振成像分析小脑形态。小鼠进行了一系列的行为测试，包括加速旋转杆、开阔场地、高架加迷宫、明暗转换箱、三室、雄性雌性互动、社会嗅觉和水t迷宫测试。膜片钳记录评价浦肯野细胞的诱发动作电位。行为表型表明，Scn8aflox/flox、L7Cre+小鼠的社交互动、运动学习和反向学习受损，重复行为和焦虑样行为增加。5个月大时，Scn8aflox/flox、L7Cre+小鼠开始出现小脑浦肯野细胞丢失和分子厚度减少。在9个月大时，Scn8aflox/flox、L7Cre+小鼠表现出更严重的小脑体积缩小和小脑浦肯野细胞数量减少，并在分子层和小脑深部核中出现额外的神经变性。Scn8aflox/flox、L7Cre+小鼠的浦肯野细胞重复性放电减少。综上所述，我们的实验表明，Scn8a在小脑浦肯野细胞中的表达缺失会导致小脑变性和一些与自闭症相关的行为。我们的研究证明了小脑浦肯野细胞中Scn8a的缺失对ASD行为缺陷特征的特殊贡献。然而，应该指出的是，我们在这里报道的观察效应是针对C57BL/6基因组型的。
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 (Scn8aflox/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 Scn8aflox/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, Scn8aflox/flox, L7Cre+ mice began to exhibit cerebellar Purkinje cell loss and reduced molecular thickness. At 9 months of age, Scn8aflox/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 Scn8aflox/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.
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影响因子：
2.7
作者：
Burne, THJ;McGrath, JJ;Mackay-Sim, A
通讯作者：
Mackay-Sim, A
影响因子：
4
作者：
Blanchard MG;Willemsen MH;Walker JB;Dib-Hajj SD;Waxman SG;Jongmans MC;Kleefstra T;van de Warrenburg BP;Praamstra P;Nicolai J;Yntema HG;Bindels RJ;Meisler MH;Kamsteeg EJ
通讯作者：
Kamsteeg EJ
影响因子：
3.5
作者：
Fatemi, S. Hossein;Aldinger, Kimberly A.;Ashwood, Paul;Bauman, Margaret L.;Blaha, Charles D.;Blatt, Gene J.;Chauhan, Abha;Chauhan, Ved;Dager, Stephen R.;Dickson, Price E.;Estes, Annette M.;Goldowitz, Dan;Heck, Detlef H.;Kemper, Thomas L.;King, Bryan H.;Martin, Loren A.;Millen, Kathleen J.;Mittleman, Guy;Mosconi, Matthew W.;Persico, Antonio M.;Sweeney, John A.;Webb, Sara J.;Welsh, John P.
通讯作者：
Welsh, John P.
影响因子：
5.3
作者：
Ha, Seungmin;Lee, Dongwon;Kim, Eunjoon
通讯作者：
Kim, Eunjoon
影响因子：
3.5
作者：
Chen, Kejian;Godfrey, Donald A.;Preston, Todd W.
通讯作者：
Preston, Todd W.