Cerebellar spreading depolarization mediates paroxysmal movement disorder

Paroxysmal kinesigenic dyskinesia (PKD) is the most common paroxysmal dyskinesia, characterized by recurrent episodes of involuntary movements provoked by sudden changes inmovement. 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.

Automated summary

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by involuntary movements triggered by sudden changes in movement, with Proline-rich transmembrane protein 2 (PRRT2) identified as a major causative gene. Research shows that PRRT2 deficiency enhances cerebellar spreading depolarization (SD), which is closely linked to dyskinetic movements, suggesting a potential target for treating related disorders.