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

Fumikazu Sano; Eiji Shigetomi; Youichi Shinozaki; Haruka Tsuzukiyama; Kozo Saito; Katsuhiko Mikoshiba; Hiroshi Horiuchi; Dennis Lawrence Cheung; Junichi Nabekura; Kanji Sugita; Masao Aihara; Schuichi Koizumi

doi:10.1172/jci.insight.135391

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

Fumikazu Sano,¹ Eiji Shigetomi,¹ Youichi Shinozaki,¹ Haruka Tsuzukiyama,¹ Kozo Saito,¹ Katsuhiko Mikoshiba,² Hiroshi Horiuchi,³ Dennis Lawrence Cheung,³ Junichi Nabekura,³ Kanji Sugita,⁴ Masao Aihara,⁴ and Schuichi Koizumi¹

Published April 8, 2021 - More info

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Abstract

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 inter-glial communication between different types of glial cells contributes to epileptogenesis, as past literature mainly focused on one type of glial cell. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contribute 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 Ca²⁺ signals mediated by IP₃R2, whereas deletion of this type of Ca²⁺ signaling reduced seizure susceptibility after status epilepticus. Immediate, but not late, pharmacological inhibition of microglial activation prevented subsequent reactive astrocytes, aberrant astrocyte Ca²⁺ signaling, and the enhanced seizure susceptibility. These findings indicate that the sequential activation of glial cells constitutes 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).

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

Fumikazu Sano,¹ Eiji Shigetomi,¹ Youichi Shinozaki,¹ Haruka Tsuzukiyama,¹ Kozo Saito,¹ Katsuhiko Mikoshiba,² Hiroshi Horiuchi,³ Dennis Lawrence Cheung,³ Junichi Nabekura,³ Kanji Sugita,⁴ Masao Aihara,⁴ and Schuichi Koizumi¹

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

Fumikazu Sano,1 Eiji Shigetomi,1 Youichi Shinozaki,1 Haruka Tsuzukiyama,1 Kozo Saito,1 Katsuhiko Mikoshiba,2 Hiroshi Horiuchi,3 Dennis Lawrence Cheung,3 Junichi Nabekura,3 Kanji Sugita,4 Masao Aihara,4 and Schuichi Koizumi1

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Fumikazu Sano,¹ Eiji Shigetomi,¹ Youichi Shinozaki,¹ Haruka Tsuzukiyama,¹ Kozo Saito,¹ Katsuhiko Mikoshiba,² Hiroshi Horiuchi,³ Dennis Lawrence Cheung,³ Junichi Nabekura,³ Kanji Sugita,⁴ Masao Aihara,⁴ and Schuichi Koizumi¹