Impaired Pre-Motor Circuit Activity and Movement in a Drosophila Model of KCNMA1-Linked Dyskinesia.
Impaired Pre-Motor Circuit Activity and Movement in a Drosophila Model of KCNMA1-Linked Dyskinesia.
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DOI：
10.1002/mds.28479
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Jepson JEC
中科院分区：
文献类型：
--
作者：
Kratschmer P;Lowe SA;Buhl E;Chen KF;Kullmann DM;Pittman A;Hodge JJL;Jepson JEC
阵发性运动障碍（PxD）的特征是不自主运动和运动前回路活动改变。致病突变提供了一种手段来理解PxDs的分子基础。然而，在许多情况下，缺乏携带相应突变的动物模型。在这里，我们利用果蝇，果蝇，研究与KCNMA1/hSlo1 BK钾通道中的功能获得（GOF）突变相关的PxD。我们的目标是在果蝇中重建等效BK（大钾）通道突变。我们试图确定这种突变如何改变体内动作电位（AP）和突触释放;测试这种突变是否破坏了前运动回路功能和运动;并定义参与运动中断的神经回路。我们使用同源重组产生了敲入果蝇模型。我们使用电生理记录和钙成像来评估AP形状，神经传递和幼虫前运动中枢模式发生器（CPG）的活动。我们使用视频跟踪和自动化系统来测量运动，并开发了一种遗传方法来将BK通道表达限制在定义的回路中。在PxD模型中，神经元AP的宽度减小，后超极化增强。我们在模型幼虫中确定了神经递质释放的钙依赖性减少、CPG功能障碍和相应的运动改变。最后，我们在成年模型果蝇中观察到异常运动和运动障碍样运动，并部分映射了GOF BK通道对胆碱能神经元运动的影响。我们的模型支持BK通道GOF和多动运动之间的联系，并提供了一个平台来剖析PxDs的机制基础。版权所有© 2021作者。运动障碍由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版
Paroxysmal dyskinesias (PxDs) are characterized by involuntary movements and altered pre‐motor circuit activity. Causative mutations provide a means to understand the molecular basis of PxDs. Yet in many cases, animal models harboring corresponding mutations are lacking. Here we utilize the fruit fly, Drosophila, to study a PxD linked to a gain‐of‐function (GOF) mutation in the KCNMA1/hSlo1 BK potassium channel. We aimed to recreate the equivalent BK (big potassium) channel mutation in Drosophila. We sought to determine how this mutation altered action potentials (APs) and synaptic release in vivo; to test whether this mutation disrupted pre‐motor circuit function and locomotion; and to define neural circuits involved in locomotor disruption. We generated a knock‐in Drosophila model using homologous recombination. We used electrophysiological recordings and calcium‐imaging to assess AP shape, neurotransmission, and the activity of the larval pre‐motor central pattern generator (CPG). We used video‐tracking and automated systems to measure movement, and developed a genetic method to limit BK channel expression to defined circuits. Neuronal APs exhibited reduced width and an enhanced afterhyperpolarization in the PxD model. We identified calcium‐dependent reductions in neurotransmitter release, dysfunction of the CPG, and corresponding alterations in movement, in model larvae. Finally, we observed aberrant locomotion and dyskinesia‐like movements in adult model flies, and partially mapped the impact of GOF BK channels on movement to cholinergic neurons. Our model supports a link between BK channel GOF and hyperkinetic movements, and provides a platform to dissect the mechanistic basis of PxDs. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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影响因子：
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