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Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy
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 mec...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982890/ https://www.ncbi.nlm.nih.gov/pubmed/33762902 http://dx.doi.org/10.3389/fnins.2021.581048 |
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author | Wengert, Eric R. Wenker, Ian C. Wagner, Elizabeth L. Wagley, Pravin K. Gaykema, Ronald P. Shin, Jung-Bum Patel, Manoj K. |
author_facet | Wengert, Eric R. Wenker, Ian C. Wagner, Elizabeth L. Wagley, Pravin K. Gaykema, Ronald P. Shin, Jung-Bum Patel, Manoj K. |
author_sort | Wengert, Eric R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7982890 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79828902021-03-23 Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy Wengert, Eric R. Wenker, Ian C. Wagner, Elizabeth L. Wagley, Pravin K. Gaykema, Ronald P. Shin, Jung-Bum Patel, Manoj K. Front Neurosci Neuroscience 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. Frontiers Media S.A. 2021-03-04 /pmc/articles/PMC7982890/ /pubmed/33762902 http://dx.doi.org/10.3389/fnins.2021.581048 Text en Copyright © 2021 Wengert, Wenker, Wagner, Wagley, Gaykema, Shin and Patel. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Wengert, Eric R. Wenker, Ian C. Wagner, Elizabeth L. Wagley, Pravin K. Gaykema, Ronald P. Shin, Jung-Bum Patel, Manoj K. Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy |
title | Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy |
title_full | Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy |
title_fullStr | Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy |
title_full_unstemmed | Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy |
title_short | Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy |
title_sort | adrenergic mechanisms of audiogenic seizure-induced death in a mouse model of scn8a encephalopathy |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982890/ https://www.ncbi.nlm.nih.gov/pubmed/33762902 http://dx.doi.org/10.3389/fnins.2021.581048 |
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