Severe deficiency of the voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Zhang, Jingliang; Chen, Xiaoling; Eaton, Muriel; Wu, Jing‐Yun; Ma, Zhixiong; Lai, Shaoyong; Park, Anthony; Ahmad, Talha S.; Que, Zhefu; Lee, Ji Hea; Xiao, Tiange; Yuan-song, LI; Wang, Yujia; Olivero-Acosta, Maria I.; Schaber, James A.; Jayant, Krishna; Yuan, Ching; Huang, Zhuo; Lanman, Nadia A.; Skarnes, William C.; Yang, Yang

doi:10.1016/j.celrep.2021.109495

Cited by 47 publications

(21 citation statements)

References 98 publications

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“…This ratio increases only slightly from 100% to 50% Na V 1.2 conditions, but then increases dramatically after 50% loss. Consistent with this, a gene-trap approach that reduces Scn2a expression by $75% also results in neuronal hyperexcitability (Zhang et al, 2021).…”

Section: Discussionmentioning

confidence: 53%

“…In addition to genetic background, it is possible that neuronal excitability may be affected by Scn2a-loss-induced changes in the function of other ion channels. Indeed, lifelong reductions in Scn2a expression by 75% are associated with an increase in input resistance and changes in the expression of several genes encoding or associated with K channels (Zhang et al, 2021). In our experiments using conditional deletion, we did not observe changes in K-channel function, assayed with either whole cell or nucleated patch voltage-clamp (Figure S1); however, it remains possible that K-channel function was altered in more distal dendritic regions that were not sampled in these experiments.…”

Section: Discussionmentioning

confidence: 99%

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Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

et al. 2021

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

et al. 2021

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“…Together, these ndings indicate that although restraint did not affect active membrane properties of PVT neurons in females, the expression of 10 voltage-gated ion channels were altered by restraint. Effects of altered mRNA expression may be negated by impaired translation, impaired protein regulation, or countered by compensatory changes in the expression or function of other voltage-gated ion channels as has been reported in rodent models of epilepsy (79). Further studies are needed to fully understand how these stress-induced changes in expression of voltage gated ion channels may regulate functional consequences of pPVT activity in male and female animals.…”

Section: Discussionmentioning

confidence: 97%

Sex differences in electrophysiological properties and voltage-gated ion channel expression in the paraventricular thalamic nucleus following repeated stress

Bhatnagar

Corbett

Urban

et al. 2022

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Habituation to repeated stress refers to a progressive reduction in the stress response following multiple exposures to the same, predictable stressor. We previously demonstrated that the posterior division of the paraventricular thalamic nucleus (pPVT) nucleus regulates habituation to 5 days of repeated restraint stress in male rats. Compared to males, female rats display impaired habituation to 5 days of restraint. To better understand how activity of pPVT neurons is differentially impacted in stressed males and females, we examined the electrophysiological properties of pPVT neurons under baseline conditions or following restraint. We report here that spontaneous excitatory post-synaptic current (sEPSC) amplitude was increased in males, but not females, following restraint. Further, resting membrane potential of pPVT neurons was more depolarized in males. This may be partially due to reduced potassium leakage in restrained males as input resistance was increased in male, but not female, rats 24 hours following 1 or 5 days of 30-minute restraint. Reduced potassium efflux during action potential firing also occurred in males following a single restraint as action potential half-width was increased following a single restraint. Restraint had limited effects on electrophysiological properties in females, although the mRNA for 10 voltage-gated ion channel subunits was altered in the pPVT of female rats. We hypothesize that restraint-induced changes in pPVT activation promote habituation in males. These findings are the first to describe a sexual dimorphism in stress-induced electrophysiological properties and voltage-gated ion channel expression in the pPVT. These results may explain, at least in part, why habituation to 5 days of restraint is disrupted in female rats.

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“…The cellular basis of how reduced Na v 1.2 function leads to seizures is not well understood. In a Na v 1.2 deficient, heterozygous Scn2a +/− mouse model, downregulation of potassium channels contributes to the elevated intrinsic excitability of cortical and striatal neurons 33 . Complete knockout of Scn2a affects potassium channel repolarisation in prefrontal pyramidal cells of a conditional mouse model.…”

Section: Discussionmentioning

confidence: 99%

Functional correlates of clinical phenotype and severity in recurrent SCN2A variants

et al. 2022

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In SCN2A-related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clamp (DAPC) and voltage clamp. Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between individuals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage clamp in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the α1 and β2 subunits of the Nav1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage clamp reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity.

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Severe deficiency of the voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Cited by 47 publications

References 98 publications

Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

Sex differences in electrophysiological properties and voltage-gated ion channel expression in the paraventricular thalamic nucleus following repeated stress

Functional correlates of clinical phenotype and severity in recurrent SCN2A variants

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