Impaired motor function in mice with cell-specific knockout of sodium channel Scn8a (NaV1.6) in cerebellar Purkinje neurons and granule cells
Impaired motor function in mice with cell-specific knockout of sodium channel Scn8a (NaV1.6) in cerebellar Purkinje neurons and granule cells
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DOI：
10.1152/jn.01193.2005
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发表时间：
2006-08-01
影响因子：
2.5
通讯作者：
Meisler, Miriam H.
中科院分区：
文献类型：
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作者：
Levin, Stephen I.;Khaliq, Zayd M.;Meisler, Miriam H.
Scn8a基因编码电压门控钠通道α亚基Na(V)1.6，在整个神经系统中广泛表达。在所有细胞中消除Scn8a的全局零突变会导致严重的运动功能障碍和过早死亡，因此无法分析Na(V)1.6在不同神经元类型中的生理作用。为了测试小脑Na(V)1.6对小鼠运动协调的影响，我们使用Cre-lox系统消除了Scn8a在浦肯野神经元（Purkinje KO）和/或颗粒神经元（颗粒KO）中的表达。而颗粒型KO小鼠只有轻微的行为缺陷，成年浦肯野KO小鼠表现出共济失调、震颤和协调性受损。在浦肯野和颗粒细胞（双KO）中缺乏Scn8a的双突变体加重了这些疾病。在从成年浦肯野KO和双KO而非颗粒KO小鼠中分离的浦肯野细胞中，复苏与瞬时河豚毒素（TTX）敏感的Na电流幅度的比例从接近15%下降到接近5%。在小脑切片中，浦肯野KO和双KO小鼠的浦肯野细胞自发放电率和最大放电率分别比对照降低了10倍和2倍，而颗粒KO小鼠则没有。此外，在浦肯野KO和双KO小鼠中，高频平行纤维EPSCs的短期可塑性相对于对照组发生了改变，而颗粒KO小鼠则没有。这些数据表明浦肯野钠通道的特化动力学直接依赖于Scn8a的表达。这些通道的缺失导致浦肯野细胞放电速率的降低以及传入平行纤维的突触特性的改变，最终导致运动行为的破坏。
The Scn8a gene encodes the voltage-gated Na channel alpha subunit Na(V)1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate Scn8a in all cells result in severe motor dysfunction and premature death, precluding analysis of the physiological role of Na(V)1.6 in different neuronal types. To test the effect of cerebellar Na(V)1.6 on motor coordination in mice, we used the Cre-lox system to eliminate Scn8a expression exclusively in Purkinje neurons (Purkinje KO) and/or granule neurons (granule KO). Whereas granule KO mice had only minor behavioral defects, adult Purkinje KO mice exhibited ataxia, tremor, and impaired coordination. These disorders were exacerbated in double mutants lacking Scn8a in both Purkinje and granule cells (double KO). In Purkinje cells isolated from adult Purkinje KO and double KO but not granule KO mice, the ratio of resurgent-to-transient tetrodotoxin-(TTX)-sensitive Na current amplitudes decreased from similar to 15 to similar to 5%. In cerebellar slices, Purkinje cell spontaneous and maximal firing rates were reduced 10-fold and twofold relative to control in Purkinje KO and double KO but not granule KO mice. Additionally, short-term plasticity of high-frequency parallel fiber EPSCs was altered relative to control in Purkinje KO and double KO but not granule KO mice. These data suggest that the specialized kinetics of Purkinje Na channels depend directly on Scn8a expression. The loss of these channels leads to a decrease in Purkinje cell firing rates as well as a modification of the synaptic properties of afferent parallel fibers, with the ultimate consequence of disrupting motor behavior.