Abstract：
Paroxysmal kinesigenic dyskinesia (PKD) is the most common paroxysmal dyskinesia, characterized by recurrent episodes of involuntary movements provoked by sudden changes in movement. Proline-rich transmembrane protein 2 (PRRT2) has been identified as the major causative gene for PKD. Here, we report that PRRT2 deficiency facilitates the induction of cerebellar spreading depolarization (SD) and inhibition of cerebellar SD prevents the occurrence of dyskinetic movements. Using Ca2+ imaging, we show that cerebellar SD depolarizes a large population of cerebellar granule cells and Purkinje cells in Prrt2-deficient mice. Electrophysiological recordings further reveal that cerebellar SD blocks Purkinje cell spiking and disturbs neuronal firing of the deep cerebellar nuclei (DCN). The resultant aberrant firing patterns in DCN are tightly, temporally coupled to dyskinetic episodes in Prrt2-deficient mice. Cumulatively, our findings uncover a pivotal role of cerebellar SD in paroxysmal dyskinesia, providing a potent target for treating PRRT2-related paroxysmal disorders.
摘要：
阵发性运动障碍（PKD）是最常见的阵发性运动障碍，其特征是由运动的突然变化引起的不自主运动的反复发作。富含脯氨酸的跨膜蛋白2（PRRT2）已被确定为PKD的主要致病基因。这里,我们报道PRRT2缺乏促进小脑播散去极化(SD)的诱导,小脑SD的抑制可防止运动障碍运动的发生.使用Ca2+成像，我们发现小脑SD可以使Prrt2缺陷小鼠的大量小脑颗粒细胞和Purkinje细胞去极化。电生理记录进一步表明，小脑SD可阻断浦肯野细胞的尖峰并干扰深小脑核（DCN）的神经元放电。在DCN中产生的异常点火模式是紧密的，与Prrt2缺陷小鼠的运动障碍发作时间相关。累计,我们的发现揭示了小脑SD在阵发性运动障碍中的关键作用，为治疗PRRT2相关的阵发性疾病提供了有效的靶标。
