Cerebellum-Related Characteristics of Scn8a-Mutant Mice
Cerebellum-Related Characteristics of Scn8a-Mutant Mice
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DOI：
10.1007/s12311-009-0110-z
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发表时间：
2009-09-01
期刊：
影响因子：
3.5
通讯作者：
Preston, Todd W.
中科院分区：
文献类型：
--
作者：
Chen, Kejian;Godfrey, Donald A.;Preston, Todd W.
在人类和小鼠基因组中定位的10个钠通道α亚基基因中，SCN8A基因主要在神经元和神经胶质细胞中表达。带有两种Scn8a零突变的小鼠-Scn8a(Med)和Scn8a(MedTg)-只能存活21-24天，但那些具有不完全突变的小鼠-Scn8a(MedJ)和Scn8a(Medjo)-以及那些只在小脑浦肯野细胞中敲除Scn8a的小鼠活到成年。在这里，我们回顾了以前对Scn8a突变小鼠小脑和相关区域的工作，并包括一些最新的免疫组织化学和微量化学结果。在Scn8a突变和基因敲除小鼠中，支持浦肯野细胞重复激发的复苏性钠电流减少。突变小鼠的浦肯野细胞极大地减少了自发活动，耳蜗背核的类似手轮细胞也是如此。浦肯野细胞投射到的区域中GABA(A)受体的上调可能部分补偿了突变小鼠中GABA(A)受体活性的降低。PEP-19免疫反应显示，Scn8a(MedJ)和Scn8a(Medjo)小鼠小脑浦肯野细胞胞体比正常小鼠稍小，其轴突，特别是Scn8a(Medjo)鼠，有时表现出与其他类型突变小鼠相似的增大。在Scn8a(MedJ)小鼠的浦肯野胞体和小脑深层核团和前庭核团的终止区，GABA样免疫反应的密度降低，但在这些区域的显微解剖样本中测得的GABA浓度并没有显著降低。在Scn8a(MedJ)小鼠的小脑相关区域，牛磺酸和谷氨酰胺的浓度显著增加，这可能表明胶质氨基酸代谢的上调。
Among ten sodium channel alpha-subunit genes mapped in human and mouse genomes, the SCN8A gene is primarily expressed in neurons and glia. Mice with two types of Scn8a null mutations-Scn8a (med) and Scn8a (medTg) -live for only 21-24 days, but those with incomplete mutations-Scn8a (medJ) and Scn8a (medJo) -and those with knockout of Scn8a only in cerebellar Purkinje cells live to adult age. We review here previous work on cerebellum and related regions of Scn8a mutant mice and include some newer immunohistochemical and microchemical results. The resurgent sodium current that underlies the repeated firing of Purkinje cells is reduced in Scn8a mutant and knockout mice. Purkinje cells of mutant mice have greatly reduced spontaneous activity, as do the analogous cartwheel cells of the dorsal cochlear nucleus. Up-regulation of GABA(A) receptors in regions to which Purkinje cells project may partially compensate for their decreased activity in the mutant mice. The somata of cerebellar Purkinje cells of Scn8a (medJ) and Scn8a (medJo) mice, as revealed by PEP-19 immunoreaction, are slightly smaller than normal, and their axons, especially in Scn8a (medJo) mice, sometimes show enlargements similar to those in other types of mutant mice. Density of GABA-like immunoreactivity is decreased in Purkinje somata and regions of termination in deep cerebellar and vestibular nuclei of Scn8a (medJ) mice, but measured GABA concentration is not significantly reduced in microdissected samples of these regions. The concentrations of taurine and glutamine are significantly increased in cerebellar-related regions of Scn8a (medJ) mice, possibly suggesting up-regulation of glial amino acid metabolism.