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

Abstract

Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy; however, it remains unknown whether such glial activation is capable of promoting epileptogenesis. 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 appear first, followed by reactive astrocytes and increased susceptibility to seizures. Pharmacological intervention against microglial activation reduces astrogliosis, aberrant astrocyte Ca2+ signaling, and seizure susceptibility. Reactive astrocytes exhibit larger Ca2+ signals mediated by IP3R2, whereas deletion of this type of Ca2+ signaling reduces seizure susceptibility after status epilepticus. Together, our findings indicate that the sequential activation of glial cells constitutes a cause of epileptogenesis after status epilepticus.