Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics.
Department of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, New York City, New York 10029.
J Neurosci. 2019 Sep 4;39(36):7195-7205. doi: 10.1523/JNEUROSCI.0407-19.2019. Epub 2019 Jul 18.
Clinical and experimental data indicate striatal cholinergic dysfunction in dystonia, a movement disorder typically resulting in twisted postures via abnormal muscle contraction. Three forms of isolated human dystonia result from mutations in the (DYT1), (DYT6), and (DYT25) genes. Experimental models carrying these mutations facilitate identification of possible shared cellular mechanisms. Recently, we reported elevated extracellular striatal acetylcholine by microdialysis and paradoxical excitation of cholinergic interneurons (ChIs) by dopamine D2 receptor (D2R) agonism using slice electrophysiology in mice. The paradoxical excitation was caused by overactive muscarinic receptors (mAChRs), leading to a switch in D2R coupling from canonical G to noncanonical β-arrestin signaling. We sought to determine whether these mechanisms in mice are shared with knock-in and knock-out dystonia models and to determine the impact of sex. We found mice of both sexes have elevated extracellular striatal acetylcholine and D2R-induced paradoxical ChI excitation, which was reversed by mAChR inhibition. Elevated extracellular acetylcholine was absent in male and female mice, but the paradoxical D2R-mediated ChI excitation was retained and only reversed by inhibition of adenosine A2ARs. The G-preferring D2R agonist failed to increase ChI excitability, suggesting a possible switch in coupling of D2Rs to β-arrestin, as seen previously in a DYT1 model. These data show that, whereas elevated extracellular acetylcholine levels are not always detected across these genetic models of human dystonia, the D2R-mediated paradoxical excitation of ChIs is shared and is caused by altered function of distinct G-protein-coupled receptors. Dystonia is a common and often disabling movement disorder. The usual medical treatment of dystonia is pharmacotherapy with nonselective antagonists of muscarinic acetylcholine receptors, which have many undesirable side effects. Development of new therapeutics is a top priority for dystonia research. The current findings, considered in context with our previous investigations, establish a role for cholinergic dysfunction across three mouse models of human genetic dystonia: DYT1, DYT6, and DYT25. The commonality of cholinergic dysfunction in these models arising from diverse molecular etiologies points the way to new approaches for cholinergic modulation that may be broadly applicable in dystonia.
临床和实验数据表明，在肌张力障碍中纹状体胆碱能功能障碍，这是一种通常导致扭曲姿势的运动障碍，其特征是肌肉异常收缩。三种孤立的人类肌张力障碍形式是由（DYT1）、（DYT6）和（DYT25）基因突变引起的。携带这些突变的实验模型有助于确定可能存在的共同细胞机制。最近，我们通过微透析报告了纹状体细胞外乙酰胆碱升高，并通过使用 切片电生理学在 小鼠中观察到多巴胺 D2 受体（D2R）激动剂引起的胆碱能中间神经元（ChIs）反常兴奋。这种反常兴奋是由过度活跃的毒蕈碱受体（mAChRs）引起的，导致 D2R 从经典的 G 蛋白偶联到非经典的β-arrestin 信号转导的偶联发生改变。我们试图确定这些机制在 小鼠中是否与 基因敲入和 基因敲除肌张力障碍模型共享，并确定性别对其的影响。我们发现，无论雌雄， 小鼠的纹状体细胞外乙酰胆碱水平升高，D2R 诱导的 ChI 反常兴奋，这可被 mAChR 抑制剂逆转。雄性和雌性 小鼠均未检测到细胞外乙酰胆碱升高，但保留了反常的 D2R 介导的 ChI 兴奋，仅可被腺苷 A2AR 抑制剂逆转。优先作用于 G 蛋白的 D2R 激动剂未能增加 ChI 兴奋性，这表明以前在 DYT1 模型中所见的 D2R 偶联可能发生了向β-arrestin 的转变。这些数据表明，尽管在这些人类肌张力障碍的遗传模型中并非总是检测到细胞外乙酰胆碱水平升高，但 D2R 介导的 ChI 反常兴奋是共享的，并且是由不同 G 蛋白偶联受体的功能改变引起的。肌张力障碍是一种常见的且通常使人致残的运动障碍。肌张力障碍的常规治疗方法是使用毒蕈碱乙酰胆碱受体的非选择性拮抗剂进行药物治疗，但这会产生许多不良的副作用。开发新的治疗方法是肌张力障碍研究的重中之重。当前的研究结果，结合我们之前的研究，在三个小鼠模型中建立了人类遗传肌张力障碍：DYT1、DYT6 和 DYT25 中胆碱能功能障碍的作用。这些源于不同分子病因的模型中胆碱能功能障碍的共同性为胆碱能调节开辟了新途径，这可能在肌张力障碍中具有广泛的适用性。
