Insights into pathophysiology and therapy from a mouse model of Dravet syndrome
Open accessAbstract
Summary: Mutations in voltage‐gated sodium channels are associated with epilepsy syndromes with a wide range of severity. Complete loss of function in the Na v 1.1 channel encoded by the SCN1A gene is associated with severe myoclonic epilepsy in infancy (SMEI), a devastating infantile‐onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications. Genetic mouse models of SMEI have been created that strikingly recapitulate the SMEI phenotype including age and temperature dependence of seizures and ataxia. Loss‐of‐function in Na v 1.1 channels results in severely impaired sodium current and action potential firing in hippocampal γ‐aminobutyric acid (GABA)ergic interneurons without detectable changes in excitatory pyramidal neurons. The resulting imbalance between excitation and inhibition likely contributes to hyperexcitability and seizures. Reduced sodium current and action potential firing in cerebellar Purkinje neurons likely contributes to comorbid ataxia. A mechanistic understanding of hyperexcitability, seizures, and comorbidities such as ataxia has led to novel strategies for treatment.
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More than 300 mutations in SCN1A exons account for about 70% of Dravet syndrome cases; most are truncations or deletions disrupting voltage sensing or ion conduction, and the remaining 30% likely act through effects on SCN1A expression.
“Identification of >300 mutations in SCN1A exons accounts for ∼70% of DS cases; and most mutations are truncations or deletions that disrupt voltage sensing or ion conduction, with the remaining 30% likely acting through their impact on SCN1A expression (Oakley et al., 2011).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Oakley et al., 2011
Decreased inhibitory firing leads to dysregulation of inhibition, the likely cause of seizures in Dravet syndrome patients.
“In turn, decreased inhibitory firing leads to dysregulation of inhibition, the likely cause of seizures in DS patients (Oakley et al., 2011).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Oakley et al., 2011
SCN1A loss-of-function impairs sodium currents and spiking in hippocampal GABAergic interneurons without a detectable effect on excitatory pyramidal neurons.
“SCN1A loss-of-function impairs sodium currents and spiking in hippocampal GABAergic interneurons, without a detectable effect on excitatory pyramidal neurons.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Oakley et al., 2011
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Cites
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- Authors
- Oakley, J. C., Kalume, F., & Catterall, W. A.
- Affiliations
- University of Washington (US)
- Corresponding author
- Catterall, William A.
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2011-04
- Volume
- 52
- Issue
- s2
- Pages
- 59-61
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- PMC
- PMC3547637
- OpenAlex
- W1597950071
- Cited by
- 68
- References
- 15
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 8 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 2 · 2016: 7 · 2015: 6 · 2014: 8 · 2013: 6 · 2012: 2
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (K01NS062862, R01NS025704)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- Dravet syndrome, SCN1A, Nav1.1 sodium channel, mouse model, GABAergic interneurons, Purkinje cells, ataxia, excitatory-inhibitory imbalance, epilepsy treatment
- MeSH terms
- Animals, Ataxia, Disease Models, Animal, Epilepsies, Myoclonic, Humans, Nerve Tissue Proteins, Syndrome, Sodium Channels, Mice, NAV1.1 Voltage-Gated Sodium Channel
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