A knock-in model of human epilepsy in Drosophila reveals a novel cellular mechanism associated with heat-induced seizure

J Neurosci. 2012 Oct 10;32(41):14145-55. doi: 10.1523/JNEUROSCI.2932-12.2012.

Abstract

Over 40 missense mutations in the human SCN1A sodium channel gene are linked to an epilepsy syndrome termed genetic epilepsy with febrile seizures plus (GEFS+). Inheritance of GEFS+ is dominant, but the underlying cellular mechanisms remain poorly understood. Here we report that knock-in of a GEFS+ SCN1A mutation (K1270T) into the Drosophila sodium channel gene, para, causes a semidominant temperature-induced seizure phenotype. Electrophysiological studies of GABAergic interneurons in the brains of adult GEFS+ flies reveal a novel cellular mechanism underlying heat-induced seizures: the deactivation threshold for persistent sodium currents reversibly shifts to a more negative voltage when the temperature is elevated. This leads to sustained depolarizations in GABAergic neurons and reduced inhibitory activity in the central nervous system. Furthermore, our data indicate a natural temperature-dependent shift in sodium current deactivation (exacerbated by mutation) may contribute to febrile seizures in GEFS+ and perhaps normal individuals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal*
  • Drosophila Proteins / genetics
  • Drosophila melanogaster
  • Epilepsy / genetics
  • Epilepsy / physiopathology
  • Epilepsy, Generalized / etiology
  • Epilepsy, Generalized / genetics*
  • Epilepsy, Generalized / physiopathology
  • Female
  • Gene Knock-In Techniques* / methods
  • Hot Temperature / adverse effects*
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation / genetics
  • NAV1.1 Voltage-Gated Sodium Channel / genetics*
  • Seizures / genetics
  • Seizures / physiopathology
  • Seizures, Febrile / etiology
  • Seizures, Febrile / genetics*
  • Seizures, Febrile / physiopathology

Substances

  • Drosophila Proteins
  • NAV1.1 Voltage-Gated Sodium Channel
  • SCN1A protein, human

Supplementary concepts

  • Generalized Epilepsy With Febrile Seizures Plus, Type 2