Differential roles of NaV1.2 and NaV1.6 in regulating neuronal excitability at febrile temperature and distinct contributions to febrile seizures

Mingyu Ye,Luping Yin,Mingpo Yang,Shan Jiang,Cuiping Tian,Yousheng Shu,Qiyu Zhu,Jun Yang

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.

Highlights

Genetic defects[2,11,12,13,14], we aimed to investigate the alternative potential underlying mechanisms of the environmentally triggered seizures
C121W which causes slower inactivation of sodium currents without affecting recovery kinetics3) is linked to GEFS+ type 1; De novo LoF mutations in SCN1A which results in reduced currents in interneurons leading to network dis-inhibition is associated with GEFS+ type 2, or Dravet syndrome[4,21]; Mutations in SCN2A (e.g. GoF mutation at p.Y1589C causes depolarizing shift of steady-state inactivation, slowed inactivation, increased persistent current and fasten recovery from inactivation22) have been associated with GEFS+, SMEI and BFNIS5,22–25; LoF mutations in SCN8A result in movement disorders and intellectual disability without seizures[26,27], while GoF mutations in SCN8A
Little is known how they behave at FT and how that may contribute to febrile seizures (FS) genesis

Summary

Introduction

Genetic defects[2,11,12,13,14], we aimed to investigate the alternative potential underlying mechanisms of the environmentally triggered seizures. Volkers et al compared temperature effects on NaV1.1 wild-type, R859H, and R865G and showed LoF gating defects in both mutants at FT38; Peters et al showed that the Dravet syndrome associated NaV1.1 mutant (p.A1273V) undergoes depolarization shifts in both steady state activation(LoF) and inactivation(GoF) at FT39. Studies in this direction could provide useful views on the mechanisms of FS at the molecular level, and could benefit rational development of treatments. Our data differentiate the temperature dependent biophysical properties of somatic and axonal sodium channels primarily NaV1.2 and NaV1.6 respectively, and reveal an important role of NaV1.2 subtype in supporting neuronal hyperactivities at FT that may induce seizures

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Conclusion