PRRT2 loss-of-function mutations have been associated with familial paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis, and benign familial infantile seizures. Dystonia is the foremost involuntary movement disorder manifest by patients with PKD. Using a lacZ reporter and quantitative reverse-transcriptase PCR, we mapped the temporal and spatial distribution of PRRT2 in mouse brain and showed the highest levels of expression in cerebellar cortex. Further investigation into PRRT2 localization within the cerebellar cortex revealed that Prrt2 transcripts reside in granule cells but not Purkinje cells or interneurons within cerebellar cortex, and PRRT2 is presynaptically localized in the molecular layer. Analysis of synapses in the cerebellar molecular layer via electron microscopy showed that Prrt2^-/- mice have increased numbers of docked vesicles but decreased vesicle numbers overall. In addition to impaired performance on several motor tasks, approximately 5% of Prrt2^-/- mice exhibited overt PKD with clear face validity manifest as dystonia. In Prrt2 mutants, we found reduced parallel fiber facilitation at parallel fiber-Purkinje cell synapses, reduced Purkinje cell excitability, and normal cerebellar nuclear excitability, establishing a potential mechanism by which altered cerebellar activity promotes disinhibition of the cerebellar nuclei, driving motor abnormalities in PKD. Overall, our findings replicate, refine, and expand upon previous work with PRRT2 mouse models, contribute to understanding of paroxysmal disorders of the nervous system, and provide mechanistic insight into the role of cerebellar cortical dysfunction in dystonia.

PRRT2功能丧失突变与家族性阵发性运动障碍 (PKD)、婴儿惊厥和舞蹈手足徐动症以及良性家族性婴儿癫痫发作有关。肌张力障碍是 PKD 患者表现出的最重要的不自主运动障碍。使用 lacZ 报告基因和定量逆转录酶 PCR，我们绘制了 PRRT2 在小鼠大脑中的时间和空间分布图，并显示小脑皮质中的表达水平最高。对 PRRT2 在小脑皮质内定位的进一步研究表明Prrt2转录本存在于颗粒细胞中，但不存在于小脑皮质内的浦肯野细胞或中间神经元中，并且 PRRT2 位于突触前分子层中。通过电子显微镜对小脑分子层突触的分析表明，Prrt2 ^-/-小鼠的停泊囊泡数量增加，但总体囊泡数量减少。除了一些运动任务的表现受损之外，大约 5% 的Prrt2 ^-/-小鼠表现出明显的 PKD，其明显的面部有效性表现为肌张力障碍。在Prrt2中在突变体中，我们发现平行纤维-浦肯野细胞突触处的平行纤维促进作用降低，浦肯野细胞兴奋性降低，小脑核兴奋性正常，建立了一种潜在机制，通过改变小脑活动促进小脑核去抑制，驱动 PKD 的运动异常。总体而言，我们的研究结果复制、完善和扩展了之前对 PRRT2 小鼠模型的研究，有助于理解神经系统的阵发性紊乱，并为小脑皮质功能障碍在肌张力障碍中的作用提供了机制见解。