Cerebellar spreading depolarization mediates paroxysmal movement disorder

Cell Rep. 2021 Sep 21;36(12):109743. doi: 10.1016/j.celrep.2021.109743.

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.

Keywords: Na(v) channel; PRRT2; Purkinje cell; cerebellar granule cell; cerebellum; deep cerebellar nuclei; dystonia; inactivation; paroxysmal kinesigenic dyskinesia; spreading depolarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium / metabolism
  • Cerebellum / physiology*
  • Dystonia / metabolism
  • Dystonia / pathology*
  • Electrocorticography
  • In Vitro Techniques
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Potassium Chloride / pharmacology
  • Purkinje Cells / physiology
  • Voltage-Gated Sodium Channel Blockers / pharmacology
  • Voltage-Gated Sodium Channels / chemistry
  • Voltage-Gated Sodium Channels / metabolism

Substances

  • Membrane Proteins
  • PRRT2 protein, mouse
  • Voltage-Gated Sodium Channel Blockers
  • Voltage-Gated Sodium Channels
  • Potassium Chloride
  • Calcium

Supplementary concepts

  • Familial paroxysmal dystonia