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

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

Author information

1
Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. my2406@cumc.columbia.edu.
2
State Key Laboratory of Cognitive Neuroscience and Learning, School of Brain and Cognitive Sciences, the Collaborative Innovation Center for Brain Science, Beijing Normal University, Beijing, China.
3
iHuman Institute, ShanghaiTech University, Shanghai, China.
4
Brain Institute, College of Pharmaceutical Sciences, Capital Medical University, Beijing, China.
5
Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
6
State Key Laboratory of Cognitive Neuroscience and Learning, School of Brain and Cognitive Sciences, the Collaborative Innovation Center for Brain Science, Beijing Normal University, Beijing, China. yousheng@bnu.edu.cn.

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.

PMID:
29335582
PMCID:
PMC5768682
DOI:
10.1038/s41598-017-17344-8
[Indexed for MEDLINE]
Free PMC Article

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