Tottering mouse motor dysfunction is abolished on the Purkinje cell degeneration (pcd) mutant background
Tottering mouse motor dysfunction is abolished on the Purkinje cell degeneration (pcd) mutant background
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DOI：
10.1006/exnr.1999.7171
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发表时间：
1999-11-01
影响因子：
5.3
通讯作者：
Hess, EJ
中科院分区：
文献类型：
--
作者：
Campbell, DB;North, JB;Hess, EJ
摇摇欲坠(TG)小鼠遗传了钙通道α(1A)亚单位基因的隐性突变，该基因编码P/Q型电压敏感钙通道的造孔蛋白，主要表达于小脑颗粒和浦肯野神经元。这种摇摇欲坠的突变的表型后果包括共济失调、多棘波放电和间歇性运动功能障碍，最好的描述是阵发性肌张力障碍。这些肌张力障碍事件诱导c-fos基因在小脑回路的表达，包括小脑颗粒和浦肯野神经元、小脑深核和深核团的突触后靶点。与该突变相关的细胞异常包括脑干核、蓝斑轴突和小脑浦肯野细胞中L类钙通道的异常表达。在这里，这两个不同的神经通路在摇摇欲坠的小鼠间歇性肌张力障碍表达中的作用被评估。用神经毒素N-(2-氯乙基)-N-乙基-2-溴苯基胺(DSP-4)损毁蓝斑轴索不影响小鼠抖动肌张力障碍发作的频率。相反，通过生成TG/TG；PCD/PCD双突变小鼠移除带有浦肯野细胞变性(PCD)突变的小脑浦肯野细胞，完全消除了摇摇欲坠的小鼠肌张力障碍。此外，限制后TG/TG；PCD/PCD双突变体的c-fos表达模式与野生型小鼠没有区别，表明PCD损伤消除了一个必要的环节。在这个异常的神经网络中。这些数据表明，突变基因大量表达的小脑皮质参与了摇摇欲坠的小鼠肌张力障碍发作的表达。(C)1999年学术出版社。
Tottering (tg) mice inherit a recessive mutation of the calcium channel alpha(1A) subunit gene, which encodes the pore-forming protein of P/Q-type voltage-sensitive calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons. The phenotypic consequences of the tottering mutation include ataxia, polyspike discharges, and an intermittent motor dysfunction best described as paroxysmal dystonia. These dystonic episodes induce c-fos mRNA expression in the cerebellar circuitry, including cerebellar granule and Purkinje neurons, deep cerebellar nuclei, and the postsynaptic targets of the deep nuclei. Cellular abnormalities associated with the mutation include hyperarborization of brainstem nucleus locus ceruleus axons and abnormal expression of L-type calcium channels in cerebellar Purkinje cells. Here, the role of these two distinct neural pathways in the expression of tottering mouse intermittent dystonia was assessed. Lesion of locus ceruleus axone with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine (DSP-4) did not affect the frequency of tottering mouse dystonic episodes. In contrast, removal of cerebellar Purkinje cells with the Purkinje cell degeneration (pcd) mutation by generation of tg/tg; pcd/pcd double mutant mice completely eliminated tottering mouse dystonia. Further, the c-fos expression pattern of tg/tg; pcd/pcd double mutants following restraint was indistinguishable from that of wild-type mice, suggesting that the pcd, lesion eliminated an essential link. in this abnormal neural network. These data suggest that the cerebellar cortex, where the mutant gene is abundantly expressed, contributes to the expression of tottering mouse dystonic episodes. (C) 1999 Academic Press.