Differential roles of Na V 1.2 and Na V 1.6 in regulating neuronal excitability at febrile temperature and distinct contributions to febrile seizures

Sci Rep. 2018 Jan 15;8(1):753. doi: 10.1038/s41598-017-17344-8.

Abstract

Dysregulation of voltage-gated sodium channels (VGSCs) is associated with multiple clinical disorders, including febrile seizures (FS). The contribution of different sodium channel subtypes to environmentally triggered seizures is not well understood. Here we demonstrate that somatic and axonal sodium channels primarily mediated through NaV1.2 and NaV1.6 subtypes, respectively, behave differentially at FT, and might play distinct roles in FS generation. In contrast to sodium channels on the main axonal trunk, somatic ones are more resistant to inactivation and display significantly augmented currents, faster gating rates and kinetics of recovery from inactivation at FT, features that promote neuronal excitabilities. Pharmacological inhibition of NaV1.2 by Phrixotoxin-3 (PTx3) suppressed FT-induced neuronal hyperexcitability in brain slice, while up-regulation of NaV1.2 as in NaV1.6 knockout mice showed an opposite effect. Consistently, NaV1.6 knockout mice were more susceptible to FS, exhibiting much lower temperature threshold and shorter onset latency than wildtype mice. Neuron modeling further suggests that NaV1.2 is the major subtype mediating FT-induced neuronal hyperexcitability, and predicts potential outcomes of alterations in sodium channel subtype composition. Together, these data reveal a role of native NaV1.2 on neuronal excitability at FT and its important contribution to FS pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials*
  • Animals
  • Disease Models, Animal
  • Mice, Knockout
  • NAV1.2 Voltage-Gated Sodium Channel / metabolism*
  • NAV1.6 Voltage-Gated Sodium Channel / deficiency
  • NAV1.6 Voltage-Gated Sodium Channel / metabolism*
  • Neurons / physiology*
  • Neurons / radiation effects
  • Seizures, Febrile / physiopathology*
  • Temperature

Substances

  • NAV1.2 Voltage-Gated Sodium Channel
  • NAV1.6 Voltage-Gated Sodium Channel
  • Scn8a protein, mouse