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

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.

Inflammatory signs and epileptic crisis in patients admitted in an emergency unit

“…Fever and tachypnea were described in most of the medical records, which are nonspecific signs that may take place in several pathologies, being present before the occurrence of epileptic seizures in epileptic patients. The relation found in the present study between the occurrence of fever concomitant with leukocytosis, during and after epileptic seizures, has been discussed in a previous (12) . The authors described increased body temperature and leukocytosis as seizure-induced inflammatory responses in patients diagnosed with epileptic seizures.…”

“…In children, the fact that fever episodes cause epileptic seizures may be explained by their higher CNS sensitivity, making this population more susceptible to febrile seizures. This is a benign and self-limiting diagnosis, affecting from 2% to 5% (12) . Thus, it can be inferred that the number of episodes of epileptic seizure can be reduced by treating the cause, in this case, the fever.…”

FGF14‐related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9

“…FGF14 also directly regulates the function of Nav1.2 and Nav1.6 channels at the axon initial segment. NaV1.2 is the main channel subtype implicated in the mediation of fever‐induced neuronal hyperexcitability 16 . This could explain why fever is a triggering factor in FGF14‐mutated patients.…”

Mutations in the Scn8a DIIS4 voltage sensor reveal new distinctions among hypomorphic and null Nav1.6 sodium channels

“…Without this increase in levels of WT VGSCs at the nodes of Ranvier, the Scn8a Δ9/Δ9 and Scn8a ∇3/∇3 homozygous mutants would demonstrate impaired nerve conduction. Though additional Western blotting and immunostaining would be necessary to confirm this hypothesis, previous studies have demonstrated that loss of Scn8a expression leads to the compensatory recruitment of other VGSC proteins, particularly Na v 1.2 (encoded by Scn2a ), to the mature nodes of Ranvier and axon initial segment . In further support of this hypothesis, Vega et al reported that Na v 1.2 protein levels are significantly upregulated in null Scn8a med‐Tg/med‐Tg mutants relative to WT littermates …”