Heat opens axon initial segment sodium channels: A febrile seizure mechanism?

Thomas, Evan A.; Hawkins, Roger J.; Richards, Kay; Xu, Ruwei; Gazina, Elena V.; Petrou, Steven

doi:10.1002/ana.21712

Cited by 49 publications

(56 citation statements)

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“…Na V 1.2 is widely expressed in pyramidal neurons across the brain including the hippocampus and has been found in both AIS and nodes of Ranvier (28,32). Although it is fairly well established that Na V 1.6 is an abundant brain Na + channel thought to mediate AP initiation at the distal end of the AIS (36), little is known about the effects of β1 subunits on this channel (46).…”

Section: Discussionmentioning

confidence: 99%

“…In order to assess whether the exclusion of mutant β1(W121) subunits from the AIS has an impact on trafficking of the pore-forming Na + channel α subunits, we examined the detailed distribution of the 3 α subunits known to reside in the AIS, Na v 1.1, Na v 1.2, and Na v 1.6 (28,(30)(31)(32). In tissue from wild-type CC mice, the distributions of these α subunits were similar to previous reports.…”

Section: Cells and Cerebellar Purkinje Neurons (mentioning

confidence: 99%

“…Previously, it has been shown that Na + channel gating rates increase with increasing temperature (32) and consequently, the kinetics of APs recorded at low temperatures are expected to be slower than APs recorded at higher temperatures. Accordingly, we found that at 22°C recording temperature, the membrane voltage acceleration was lower (Supplemental Figure 5) and AIS to soma delay was increased ( Figure 6G).…”

Section: Figurementioning

confidence: 99%

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Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

Wimmer¹,

Reid²,

Mitchell³

et al. 2010

J. Clin. Invest.

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Febrile seizures are a common childhood seizure disorder and a defining feature of genetic epilepsy with febrile seizures plus (GEFS+), a syndrome frequently associated with Na + channel mutations. Here, we describe the creation of a knockin mouse heterozygous for the C121W mutation of the β1 Na + channel accessory subunit seen in patients with GEFS+. Heterozygous mice with increased core temperature displayed behavioral arrest and were more susceptible to thermal challenge than wild-type mice. Wild-type β1 was most concentrated in the membrane of axon initial segments (AIS) of pyramidal neurons, while the β1(C121W) mutant subunit was excluded from AIS membranes. In addition, AIS function, an indicator of neuronal excitability, was substantially enhanced in hippocampal pyramidal neurons of the heterozygous mouse specifically at higher temperatures. Computational modeling predicted that this enhanced excitability was caused by hyperpolarized voltage activation of AIS Na + channels. This heat-sensitive increased neuronal excitability presumably contributed to the heightened thermal seizure susceptibility and epileptiform discharges seen in patients and mice with β1(C121W) subunits. We therefore conclude that Na + channel β1 subunits modulate AIS excitability and that epilepsy can arise if this modulation is impaired.

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Section: Discussionmentioning

confidence: 99%

Section: Cells and Cerebellar Purkinje Neurons (mentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

Wimmer¹,

Reid²,

Mitchell³

et al. 2010

J. Clin. Invest.

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“…14 Whether temperature affects the voltage dependence of gating in native channels is debatable. A large number of studies show little or no effect of temperature on the voltage of halfmaximal (V 1/2 ) steady-state activation, 10,[15][16][17][18][19][20] but Thomas et al (2009) shows a strong hyperpolarizing shift in the V 1/2 of activation with increased temeperature. 11 The V 1/2 of inactivation, specifically slow inactivation, seems to show stronger temperature sensitivity.…”

mentioning

confidence: 99%

“…A large number of studies show little or no effect of temperature on the voltage of halfmaximal (V 1/2 ) steady-state activation, 10,[15][16][17][18][19][20] but Thomas et al (2009) shows a strong hyperpolarizing shift in the V 1/2 of activation with increased temeperature. 11 The V 1/2 of inactivation, specifically slow inactivation, seems to show stronger temperature sensitivity. 10,12,15,[21][22][23][24] The larger temperature sensitivity of slow inactivation may reflect the greater number of state transitions required to complete slow inactivation in comparison to fast inactivation.…”

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confidence: 99%

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Egri

Ruben

2012

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Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture

Harris,

Oliver,

Perucca

et al. 2023

Annals of Neurology

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ObjectiveFamilial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE.MethodsWe studied 134 families with ≥ 2 first or second‐degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls.ResultsThe age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13–28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug‐resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed.InterpretationFMTLE is a generally mild drug‐responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub‐genome‐wide significant focal epilepsy genome‐wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023

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Heat opens axon initial segment sodium channels: A febrile seizure mechanism?

Abstract: The direct effect of heat on ion channels localized to the site of action potential initiation potentially causes a profound increase in neuronal excitability. This is likely to contribute to febrile seizure genesis.

Cited by 49 publications

References 42 publications

Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

A hot topic

Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture

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