A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

Neuroscience. 2001;102(2):307-17. doi: 10.1016/s0306-4522(00)00479-6.


The GAL879-881QQQ mutation in the cytoplasmic S4-S5 linker of domain 2 of the rat brain IIA sodium channel (Na(v)1.2) results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice began at two months of age and were accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous electroencephalogram monitoring detected focal seizure activity in the hippocampus, which in some instances generalized to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibited increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there was extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice was shortened and only 25% of the mice survived beyond six months of age. Four independent transgenic lines expressing the wild-type sodium channel were examined and did not exhibit any abnormalities. The transgenic Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is a candidate gene for seizure disorders mapped to chromosome 2q22-24.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal
  • Cells, Cultured
  • Disease Models, Animal
  • Disease Progression
  • Electroencephalography
  • Epilepsy / genetics*
  • Epilepsy / physiopathology*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Mice
  • Mice, Transgenic
  • Mutation*
  • NAV1.2 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Oocytes / cytology
  • Oocytes / metabolism
  • Organ Specificity
  • Patch-Clamp Techniques
  • Sodium / metabolism
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism
  • Stereotyped Behavior*
  • Survival Rate
  • Transfection
  • Transgenes
  • Xenopus


  • NAV1.2 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • SCN2A protein, human
  • Scn2A protein, rat
  • Scn2a protein, mouse
  • Sodium Channels
  • Sodium