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Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy

We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus fo...

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Autores principales: Wong, Jennifer C., Makinson, Christopher D., Lamar, Tyra, Cheng, Qi, Wingard, Jeffrey C., Terwilliger, Ernest F., Escayg, Andrew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760706/
https://www.ncbi.nlm.nih.gov/pubmed/29317669
http://dx.doi.org/10.1038/s41598-017-17786-0
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author Wong, Jennifer C.
Makinson, Christopher D.
Lamar, Tyra
Cheng, Qi
Wingard, Jeffrey C.
Terwilliger, Ernest F.
Escayg, Andrew
author_facet Wong, Jennifer C.
Makinson, Christopher D.
Lamar, Tyra
Cheng, Qi
Wingard, Jeffrey C.
Terwilliger, Ernest F.
Escayg, Andrew
author_sort Wong, Jennifer C.
collection PubMed
description We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy. Using a small-hairpin-interfering RNA directed against the Scn8a gene, we selectively reduced Scn8a expression in the hippocampus of the intrahippocampal kainic acid (KA) mouse model of mesial temporal lobe epilepsy. We found that Scn8a knockdown prevented the development of spontaneous seizures in 9/10 mice, ameliorated KA-induced hyperactivity, and reduced reactive gliosis. These results support the potential of selectively targeting Scn8a for the treatment of refractory epilepsy.
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spelling pubmed-57607062018-01-17 Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy Wong, Jennifer C. Makinson, Christopher D. Lamar, Tyra Cheng, Qi Wingard, Jeffrey C. Terwilliger, Ernest F. Escayg, Andrew Sci Rep Article We previously found that genetic mutants with reduced expression or activity of Scn8a are resistant to induced seizures and that co-segregation of a mutant Scn8a allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, Scn8a expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to Scn8a as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of Scn8a in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy. Using a small-hairpin-interfering RNA directed against the Scn8a gene, we selectively reduced Scn8a expression in the hippocampus of the intrahippocampal kainic acid (KA) mouse model of mesial temporal lobe epilepsy. We found that Scn8a knockdown prevented the development of spontaneous seizures in 9/10 mice, ameliorated KA-induced hyperactivity, and reduced reactive gliosis. These results support the potential of selectively targeting Scn8a for the treatment of refractory epilepsy. Nature Publishing Group UK 2018-01-09 /pmc/articles/PMC5760706/ /pubmed/29317669 http://dx.doi.org/10.1038/s41598-017-17786-0 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wong, Jennifer C.
Makinson, Christopher D.
Lamar, Tyra
Cheng, Qi
Wingard, Jeffrey C.
Terwilliger, Ernest F.
Escayg, Andrew
Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy
title Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy
title_full Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy
title_fullStr Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy
title_full_unstemmed Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy
title_short Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy
title_sort selective targeting of scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760706/
https://www.ncbi.nlm.nih.gov/pubmed/29317669
http://dx.doi.org/10.1038/s41598-017-17786-0
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