Action potential broadening in a presynaptic channelopathy

Nat Commun. 2016 Jul 6:7:12102. doi: 10.1038/ncomms12102.

Abstract

Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca(2+) influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Animals
  • Ataxia / genetics
  • Ataxia / metabolism
  • Ataxia / physiopathology*
  • Calcium / metabolism
  • Channelopathies / genetics
  • Channelopathies / metabolism
  • Channelopathies / physiopathology*
  • Disease Models, Animal
  • Elapid Venoms / pharmacology
  • Female
  • Gene Expression
  • Kv1.1 Potassium Channel / antagonists & inhibitors
  • Kv1.1 Potassium Channel / genetics
  • Kv1.1 Potassium Channel / metabolism*
  • Mice
  • Mice, Transgenic
  • Microtomy
  • Mutation
  • Myokymia / genetics
  • Myokymia / metabolism
  • Myokymia / physiopathology*
  • Patch-Clamp Techniques
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / pathology
  • Purkinje Cells / drug effects
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology
  • Synaptic Transmission / drug effects
  • Tissue Culture Techniques
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Elapid Venoms
  • Kv1.1 Potassium Channel
  • gamma-Aminobutyric Acid
  • dendrotoxin
  • Calcium

Supplementary concepts

  • Episodic Ataxia, Type 1