Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice
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Key points: Inappropriate electrochemical signalling between neurons is a central problem in epilepsy. Only a fraction of all heritable epilepsies are solved, and many are due to ion channel mutations. Ion channels are cell surface molecules that initiate and coordinate electrochemical signalling, by allowing the right combination of ions to flow in and out of a neuron. Ion channels may be regulated by other genes. We recently determined that the RNA‐binding protein, ‘CELF4’, affects expression of many molecules, including ion channels, to coordinate electrochemical signalling. Here we conclude that a sodium channel called Na v 1.6 is the primary instigator of abnormal excitation when CELF4 is impaired. Na v 1.6 expression is increased in the axon initial segment – a part of the neuron that initiates electrical activity – altering intrinsic excitability. We surmise that in a brain that already has difficulty regulating other molecules due to CELF4 deficiency, this leads to uncontrolled network excitation and seizures. Abstract Mice deficient for CELF4, a neuronal RNA‐binding protein, have a complex seizure disorder that includes both convulsive and non‐convulsive seizures, and is dependent upon Celf4 gene dosage and mouse strain background. It was previously shown that Celf4 is expressed predominantly in excitatory neurons, and that deficiency results in abnormal excitatory synaptic neurotransmission. To examine the physiological and molecular basis of this, we studied Celf4‐deficient neurons in brain slices. Assessment of intrinsic properties of layer V cortical pyramidal neurons showed that neurons from mutant heterozygotes and homozygotes have a lower action potential (AP) initiation threshold and a larger AP gain when compared with wild‐type neurons. Celf4 mutant neurons also demonstrate an increase in persistent sodium current (INaP) and a hyperpolarizing shift in the voltage dependence of activation. As part of a related study, we find that CELF4 directly binds Scn8a mRNA, encoding sodium channel Na v 1.6, the primary instigator of AP at the axon initial segment (AIS) and the main carrier of INaP. In the present study we find that CELF4 deficiency results in a dramatic elevation in the expression of Na v 1.6 protein at the AIS in both null and heterozygous neurons. Together these results suggest that activation of Na v 1.6 plays a crucial role in seizure generation in this complex model of neurological disease.
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Celf4 mutant mice show aberrations in sodium channel function and increased susceptibility to seizures.
“Celf4 mutant mice show aberrations in sodium channel function, perhaps through increased NAv 1.6 in the axon initial segment of excitatory neurons, and increased susceptibility to seizures.27”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [27]
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- Authors
- Sun, W., Wagnon, J. L., Mahaffey, C. L., Briese, M., Ule, J., & Frankel, W. N.
- Affiliations
- Jackson Laboratory (US)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Frankel, Wayne N.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2012-12-05
- Volume
- 591
- Issue
- 1
- Pages
- 241-255
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC3630783
- OpenAlex
- W1576990807
- Cited by
- 36
- References
- 79
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 6 · 2013: 4
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Wellcome Trust (089701)
- National Cancer Institute (P30CA034196)
- National Institute of Neurological Disorders and Stroke (NS061971, R56NS061971, R01NS061971)
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CELF4, Nav1.6 sodium channel, epilepsy, RNA-binding proteins, axon initial segment, persistent sodium current, intrinsic excitability, action potential threshold, cortical pyramidal neurons, ion channel modulation, gene dosage
- MeSH terms
- CELF Proteins, Animals, Brain, Male, Mice, Inbred C57BL, Neurons, Seizures, Tamoxifen, RNA-Binding Proteins, Mice, Knockout, Mice, NAV1.6 Voltage-Gated Sodium Channel
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