ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Activity-dependent alternative splicing increases persistent sodium current and promotes seizure.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 67 citations in OpenAlex.
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- Rat Spinal Cord Injury Associated with Spasticity Leads to Widespread Changes in the Regulation of Retained Introns.Neurotrauma reports · 2022Article
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- Transcriptome Analysis Reveals Higher Levels of Mobile Element-Associated Abnormal Gene Transcripts in Temporal Lobe Epilepsy Patients.Frontiers in genetics · 2021Article
- Alternative polyadenylation of mRNA and its role in cancer.Genes & diseases · 2021Review
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- One Actor, Multiple Roles: The Performances of Cryptochrome inFrontiers in physiology · 2020Review
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- Conservation of alternative splicing in sodium channels reveals evolutionary focus on release from inactivation and structural insights into gating.The Journal of physiology · 2017Article
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- Seizure control through genetic and pharmacological manipulation of Pumilio in Drosophila: a key component of neuronal homeostasis.Disease models & mechanisms · 2017Article
- Transcriptional Reorganization ofFrontiers in molecular neuroscience · 2017Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Activity of voltage-gated Na channels (Na(v)) is modified by alternative splicing. However, whether altered splicing of human Na(v)s contributes to epilepsy remains to be conclusively shown. We show here that altered splicing of the Drosophila Na(v) (paralytic, DmNa(v)) contributes to seizure-like behavior in identified seizure mutants. We focus attention on a pair of mutually exclusive alternate exons (termed K and L), which form part of the voltage sensor (S4) in domain III of the expressed channel. The presence of exon L results in a large, non-inactivating, persistent I(Nap). Many forms of human epilepsy are associated with an increase in this current. In wild-type (WT) Drosophila larvae, ∼70-80% of DmNa(v) transcripts contain exon L, and the remainder contain exon K. Splicing of DmNa(v) to include exon L is increased to ∼100% in both the slamdance and easily-shocked seizure mutants. This change to splicing is prevented by reducing synaptic activity levels through exposure to the antiepileptic phenytoin or the inhibitory transmitter GABA. Conversely, enhancing synaptic activity in WT, by feeding of picrotoxin is sufficient to increase I(Nap) and promote seizure through increased inclusion of exon L to 100%. We also show that the underlying activity-dependent mechanism requires the presence of Pasilla, an RNA-binding protein. Finally, we use computational modeling to show that increasing I(Nap) is sufficient to potentiate membrane excitability consistent with a seizure phenotype. Thus, increased synaptic excitation favors inclusion of exon L, which, in turn, further increases neuronal excitability. Thus, at least in Drosophila, this self-reinforcing cycle may promote the incidence of seizure.
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