ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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Who cites it
92 citing papers in PubMed, 161 citations in OpenAlex.
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- Input-and cell-type-specific developmental alterations to thalamic synapses in a Dravet syndrome mouse model.bioRxiv : the preprint server for biology · 2026Article
- Spatiotemporal patterns of gene expression changes in the mouse dentate gyrus following entorhinal denervation.Frontiers in molecular neuroscience · 2026Article
- Defining the Cis-Regulatory Elements of SCN1A in GABAergic Interneurons.Molecular neurobiology · 2025Article
- Cell-type-specific networks during hippocampal seizures at the micro- and macroscale.Brain : a journal of neurology · 2025Article
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- Emerging Insights into the Pathogenic Mechanisms of Dravet Syndrome.Neurochemical research · 2025Review
- In vitro human ion channel assays predictive of drug-induced seizure.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Mechanisms underlying CSD initiation implicated by genetic mouse models of migraine.The journal of headache and pain · 2025Review
- Voltage-gated sodium channels in genetic epilepsy: up and down of excitability.Journal of neurochemistry · 2024Review
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- Heterozygous expression of aeLife · 2024Article
- Heterozygous expression of abioRxiv : the preprint server for biology · 2024Article
- Exploring Kainic Acid-Induced Alterations in Circular Tripartite Networks with Advanced Analysis Tools.eNeuro · 2024Article
- Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to low-voltage-fast onset seizures in Dravet syndrome.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
32 more citing papers are in PubMed but not listed here.
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13 authors at 5 institutions in 3 countries.
Funding
Abstract
Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.
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