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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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Detalles Bibliográficos
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
Descripción
Sumario: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).