RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2

Neurobiol Dis. 2014 Aug:68:47-56. doi: 10.1016/j.nbd.2014.04.005. Epub 2014 Apr 21.


Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease.

Keywords: Acetazolamide; Ataxia; Cerebellum; Mouse; P/Q-type calcium channel; Purkinje neuron; RNA interference.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia / etiology*
  • Ataxia / genetics
  • Ataxia / pathology
  • Ataxia / physiopathology
  • Calcium Channels, N-Type / genetics
  • Calcium Channels, N-Type / metabolism*
  • Cerebellum / metabolism
  • Cerebellum / pathology*
  • Disease Models, Animal
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Movement / physiology
  • Nystagmus, Pathologic / etiology*
  • Nystagmus, Pathologic / genetics
  • Nystagmus, Pathologic / pathology
  • Nystagmus, Pathologic / physiopathology
  • Postural Balance / genetics
  • Purkinje Cells / metabolism*
  • RNA Interference / physiology*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / physiology*
  • Transduction, Genetic


  • Calcium Channels, N-Type
  • RNA, Small Interfering
  • voltage-dependent calcium channel (P-Q type)
  • Green Fluorescent Proteins

Supplementary concepts

  • Episodic Ataxia, Type 2