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Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus

Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy. However, it remains unclear whether activated glial cells contribute to epileptogenesis, i.e., the chronically persistent process leading to epilepsy. Particularly, it is not cle...

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Autores principales: Sano, Fumikazu, Shigetomi, Eiji, Shinozaki, Youichi, Tsuzukiyama, Haruka, Saito, Kozo, Mikoshiba, Katsuhiko, Horiuchi, Hiroshi, Cheung, Dennis Lawrence, Nabekura, Junichi, Sugita, Kanji, Aihara, Masao, Koizumi, Schuichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262323/
https://www.ncbi.nlm.nih.gov/pubmed/33830944
http://dx.doi.org/10.1172/jci.insight.135391
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author Sano, Fumikazu
Shigetomi, Eiji
Shinozaki, Youichi
Tsuzukiyama, Haruka
Saito, Kozo
Mikoshiba, Katsuhiko
Horiuchi, Hiroshi
Cheung, Dennis Lawrence
Nabekura, Junichi
Sugita, Kanji
Aihara, Masao
Koizumi, Schuichi
author_facet Sano, Fumikazu
Shigetomi, Eiji
Shinozaki, Youichi
Tsuzukiyama, Haruka
Saito, Kozo
Mikoshiba, Katsuhiko
Horiuchi, Hiroshi
Cheung, Dennis Lawrence
Nabekura, Junichi
Sugita, Kanji
Aihara, Masao
Koizumi, Schuichi
author_sort Sano, Fumikazu
collection PubMed
description Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy. However, it remains unclear whether activated glial cells contribute to epileptogenesis, i.e., the chronically persistent process leading to epilepsy. Particularly, it is not clear whether interglial communication between different types of glial cells contributes to epileptogenesis, because past literature has mainly focused on one type of glial cell. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contributed to epileptogenesis in a drug-induced status epilepticus model. We found that reactive microglia appeared first, followed by reactive astrocytes and increased susceptibility to seizures. Reactive astrocytes exhibited larger Ca(2+) signals mediated by IP(3)R2, whereas deletion of this type of Ca(2+) signaling reduced seizure susceptibility after status epilepticus. Immediate, but not late, pharmacological inhibition of microglial activation prevented subsequent reactive astrocytes, aberrant astrocyte Ca(2+) signaling, and the enhanced seizure susceptibility. These findings indicate that the sequential activation of glial cells constituted a cause of epileptogenesis after status epilepticus. Thus, our findings suggest that the therapeutic target to prevent epilepsy after status epilepticus should be shifted from microglia (early phase) to astrocytes (late phase).
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spelling pubmed-82623232021-07-13 Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus Sano, Fumikazu Shigetomi, Eiji Shinozaki, Youichi Tsuzukiyama, Haruka Saito, Kozo Mikoshiba, Katsuhiko Horiuchi, Hiroshi Cheung, Dennis Lawrence Nabekura, Junichi Sugita, Kanji Aihara, Masao Koizumi, Schuichi JCI Insight Research Article Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy. However, it remains unclear whether activated glial cells contribute to epileptogenesis, i.e., the chronically persistent process leading to epilepsy. Particularly, it is not clear whether interglial communication between different types of glial cells contributes to epileptogenesis, because past literature has mainly focused on one type of glial cell. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contributed to epileptogenesis in a drug-induced status epilepticus model. We found that reactive microglia appeared first, followed by reactive astrocytes and increased susceptibility to seizures. Reactive astrocytes exhibited larger Ca(2+) signals mediated by IP(3)R2, whereas deletion of this type of Ca(2+) signaling reduced seizure susceptibility after status epilepticus. Immediate, but not late, pharmacological inhibition of microglial activation prevented subsequent reactive astrocytes, aberrant astrocyte Ca(2+) signaling, and the enhanced seizure susceptibility. These findings indicate that the sequential activation of glial cells constituted a cause of epileptogenesis after status epilepticus. Thus, our findings suggest that the therapeutic target to prevent epilepsy after status epilepticus should be shifted from microglia (early phase) to astrocytes (late phase). American Society for Clinical Investigation 2021-05-10 /pmc/articles/PMC8262323/ /pubmed/33830944 http://dx.doi.org/10.1172/jci.insight.135391 Text en © 2021 Sano et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Sano, Fumikazu
Shigetomi, Eiji
Shinozaki, Youichi
Tsuzukiyama, Haruka
Saito, Kozo
Mikoshiba, Katsuhiko
Horiuchi, Hiroshi
Cheung, Dennis Lawrence
Nabekura, Junichi
Sugita, Kanji
Aihara, Masao
Koizumi, Schuichi
Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
title Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
title_full Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
title_fullStr Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
title_full_unstemmed Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
title_short Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
title_sort reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262323/
https://www.ncbi.nlm.nih.gov/pubmed/33830944
http://dx.doi.org/10.1172/jci.insight.135391
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