4.6 Article

Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy

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FRONTIERS IN NEUROSCIENCE
卷 15, 期 -, 页码 -

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FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2021.581048

关键词

SUDEP; SCN8A encephalopathy; respiratory arrest; adrenergic receptors; audiogenic seizures

资金

  1. National Institutes of Health [R01NS103090, 1F31NS115451-01, R01DC014254, F31DC017370]

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This study demonstrates that mice harboring an Scn8a allele with a patient-derived mutation are susceptible to audiogenic seizures and seizure-induced death, providing a new model for studying seizure-induced death. Activation of adrenergic receptors is necessary and sufficient for recovery of breathing and prevention of seizure-induced death in this novel audiogenic seizure-induced death model.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death amongst patients whose seizures are not adequately controlled by current therapies. Patients with SCN8A encephalopathy have an elevated risk for SUDEP. While transgenic mouse models have provided insight into the molecular mechanisms of SCN8A encephalopathy etiology, our understanding of seizure-induced death has been hampered by the inability to reliably trigger both seizures and seizure-induced death in these mice. Here, we demonstrate that mice harboring an Scn8a allele with the patient-derived mutation N1768D (D/+) are susceptible to audiogenic seizures and seizure-induced death. In adult D/+ mice, audiogenic seizures are non-fatal and have nearly identical behavioral, electrographical, and cardiorespiratory characteristics as spontaneous seizures. In contrast, at postnatal days 20-21, D/+ mice exhibit the same seizure behavior, but have a significantly higher incidence of seizure-induced death following an audiogenic seizure. Seizure-induced death was prevented by either stimulating breathing via mechanical ventilation or by acute activation of adrenergic receptors. Conversely, in adult D/+ mice inhibition of adrenergic receptors converted normally non-fatal audiogenic seizures into fatal seizures. Taken together, our studies show that in our novel audiogenic seizure-induced death model adrenergic receptor activation is necessary and sufficient for recovery of breathing and prevention of seizure-induced death.

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