Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current

J Neurophysiol. 2014 Aug 15;112(4):903-12. doi: 10.1152/jn.00135.2014. Epub 2014 May 7.


Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A mutations cause distinct phenotypes in Drosophila as they do in humans, this study focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder termed Dravet syndrome (DS). Introduction of the DS SCN1A mutation (S1231R) into the Drosophila sodium channel gene para results in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS.

Keywords: Dravet syndrome; Drosophila; GEFS+; SCN1A epilepsy; sodium channel.

Publication types

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

MeSH terms

  • 5-Hydroxytryptophan / metabolism
  • Action Potentials*
  • Animals
  • Brain / cytology
  • Brain / metabolism
  • Brain / physiopathology
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila / physiology
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / metabolism
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / physiology
  • Interneurons / metabolism
  • Interneurons / physiology
  • Mutation, Missense
  • NAV1.1 Voltage-Gated Sodium Channel / genetics*
  • NAV1.1 Voltage-Gated Sodium Channel / metabolism
  • Phenotype
  • Serotonin / metabolism
  • Sodium / metabolism*


  • NAV1.1 Voltage-Gated Sodium Channel
  • Serotonin
  • Sodium
  • 5-Hydroxytryptophan