Alteration of the cholinergic system and motor deficits in cholinergic neuron-specific Dyt1 knockout mice.
Alteration of the cholinergic system and motor deficits in cholinergic neuron-specific Dyt1 knockout mice.
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DOI：
10.1016/j.nbd.2021.105342
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发表时间：
2021-07
影响因子：
6.1
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Liu Y;Xing H;Sheng W;Singh KN;Korkmaz AG;Comeau C;Anika M;Ernst A;Yokoi F;Vaillancourt DE;Frazier CJ;Li Y
肌张力障碍是一种神经性运动障碍，其特征在于持续或间歇性肌肉收缩、重复运动，有时甚至是异常姿势。DYT 1肌张力障碍是最常见的遗传性肌张力障碍之一，大多数患者携带杂合DYT 1 ΔGAG突变，导致蛋白torsinA的谷氨酸丢失。患者可以用抗胆碱能药物治疗，如苯海索，提示胆碱能状态异常。Dyt 1缺失与ChI特异性Dyt 1条件性敲除小鼠（Dyt 1 Ch 1 KO）的细胞自主效应的早期工作揭示了纹状体ChI对毒蕈碱和喹吡罗的异常电生理反应，运动障碍，并且ChI的数量或大小没有变化。然而，用于衍生Dyt 1 Ch 1 KO小鼠的Chat-cre系含有新霉素盒，据报道具有异位cre介导的重组。在这项研究中，我们通过去除Dyt 1 Ch 1 KO小鼠中的新霉素盒来产生Dyt 1 Ch 2KO小鼠系。Dyt 1 Ch 2KO小鼠表现出异常的爪紧握行为，运动协调和平衡缺陷，运动学习受损，纹状体胆碱乙酰转移酶蛋白水平降低，纹状体ChI数量减少。此外，突变体纹状体ChIs具有正常的毒蕈碱抑制功能，受损的喹吡罗介导的抑制，并改变电流密度。我们的研究结果表明，Dyt 1缺失对纹状体ChIs的细胞自主效应和纹状体ChIs和皮质纹状体通路在DYT 1肌张力障碍的发病机制中的关键作用。
Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, repetitive movement, and sometimes abnormal postures. DYT1 dystonia is one of the most common genetic dystonias, and most patients carry heterozygous DYT1 ΔGAG mutations causing a loss of a glutamic acid of the protein torsinA. Patients can be treated with anticholinergics, such as trihexyphenidyl, suggesting an abnormal cholinergic state. Early work on the cell-autonomous effects of Dyt1 deletion with ChI-specific Dyt1 conditional knockout mice (Dyt1 Ch1KO) revealed abnormal electrophysiological responses of striatal ChIs to muscarine and quinpirole, motor deficits, and no changes in the number or size of the ChIs. However, the Chat-cre line that was used to derive Dyt1 Ch1KO mice contained a neomycin cassette and was reported to have ectopic cre-mediated recombination. In this study, we generated a Dyt1 Ch2KO mouse line by removing the neomycin cassette in Dyt1 Ch1KO mice. The Dyt1 Ch2KO mice showed abnormal paw clenching behavior, motor coordination and balance deficits, impaired motor learning, reduced striatal choline acetyltransferase protein level, and a reduced number of striatal ChIs. Furthermore, the mutant striatal ChIs had a normal muscarinic inhibitory function, impaired quinpirole-mediated inhibition, and altered current density. Our findings demonstrate a cell-autonomous effect of Dyt1 deletion on the striatal ChIs and a critical role for the striatal ChIs and corticostriatal pathway in the pathogenesis of DYT1 dystonia.
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影响因子：
16.2
作者：
Chuhma N;Mingote S;Moore H;Rayport S
通讯作者：
Rayport S
影响因子：
25
作者：
Ding, Jun;Guzman, Jaime N.;Surmeier, D. James
通讯作者：
Surmeier, D. James
影响因子：
8.6
作者：
Albanese, Alberto;Bhatia, Kailash;Bressman, Susan B.;DeLong, Mahlon R.;Fahn, Stanley;Fung, Victor S. C.;Hallett, Mark;Jankovic, Joseph;Jinnah, Hyder A.;Klein, Christine;Lang, Anthony E.;Mink, Jonathan W.;Teller, Jan K.
通讯作者：
Teller, Jan K.
影响因子：
3.3
作者：
Fernagut, PO;Diguet, E;Tison, F
通讯作者：
Tison, F
影响因子：
6.1
作者：
Grundmann, K.;Reischmann, B.;Riess, O.
通讯作者：
Riess, O.