ArticleBrain : a journal of neurology2019
Prominent role of forebrain excitatory neurons in SCN8A encephalopathy.
Article in Brain : a journal of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers, 1 of them a synthesis that pooled it.
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Who cites it
70 citing papers in PubMed, 1 synthesis or guideline pooled it, 100 citations in OpenAlex.
- Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers.Pflugers Archiv : European journal of physiology · 2024Pooled it
- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
- Article
- Distinct neuronal mechanisms for motor impairment and seizures in a novel mouse model of SCN8A epileptic encephalopathy.Neurobiology of disease · 2026Article
- Base editing rescues seizures and sudden death in a SCN8A mutation-associated developmental epileptic encephalopathy model.The Journal of clinical investigation · 2026Article
- Metabolic Alterations Induced by a Seizure-Causing Sodium Channel Mutation and their Partial Normalization by Dietary α-Linolenic Acid in Drosophila.Neurochemical research · 2026Article
- Neurologist's Black Swan: Molecular Basis of Prenatal Seizures.International journal of molecular sciences · 2025Review
- Diverse species of animal models in epilepsy research: Progress and perspectives.Zoological research · 2025Review
- A splice-switching antisense oligonucleotide approach for pediatric genetic epilepsies.bioRxiv : the preprint server for biology · 2025Article
- Effects of a Gain-of-Function Mutation in the Voltage-Gated Sodium Channel Gene, and of Dietary α-Linolenic Acid Supplementation, on Whole-Body Metabolism in Drosophila.Research square · 2025Article
- Transgenic mouse models of sodium and potassium channelopathies in epilepsy: insights into disease mechanisms and therapeutics.Bioscience reports · 2025Review
- Cortical versus hippocampal network dysfunction in a human brain assembloid model of epilepsy and intellectual disability.Cell reports · 2025Article
- A research roadmap for SCN8A-related disorders: addressing knowledge gaps and aligning research priorities across stakeholders.Orphanet journal of rare diseases · 2025Article
- Article
- Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism.eLife · 2025Article
- Prenatal opioid exposure alters pain perception and increases long-term health risks in infants with neonatal opioid withdrawal syndrome.Frontiers in pain research (Lausanne, Switzerland) · 2025Article
- Voltage-gated sodium channels in genetic epilepsy: up and down of excitability.Journal of neurochemistry · 2024Review
- Allele-Specific Editing of a Dominant SCN8A Epilepsy Variant Protects against Seizures and Lethality in a Murine Model.Annals of neurology · 2024Article
- Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy.JCI insight · 2024Article
- Dentate gyrus granule cells are a locus of pathology in Scn8a developmental encephalopathy.Neurobiology of disease · 2024Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.
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