Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus
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DOI：
10.1172/jci.insight.135391
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发表时间：
2021-05-10
期刊：
影响因子：
8
通讯作者：
Koizumi, Schuichi
中科院分区：
文献类型：
--
作者：
Sano, Fumikazu;Shigetomi, Eiji;Koizumi, Schuichi
在癫痫的各种动物模型中，潜伏期内神经胶质细胞的广泛激活已经被很好地记录下来。然而，目前尚不清楚激活的神经胶质细胞是否参与了癫痫的发生，即导致癫痫的慢性持续性过程。尤其是，不同类型的胶质细胞之间的神经胶质间通讯是否有助于癫痫的发生尚不清楚，因为过去的文献主要集中在一种类型的胶质细胞上。在这里，我们展示了在药物诱导的癫痫持续状态模型中，小胶质细胞和星形胶质细胞在时间上不同的激活特征共同促进了癫痫的发生。我们发现反应性小胶质细胞首先出现，其次是反应性星形胶质细胞，增加了对癫痫的易感性。反应性星形胶质细胞表现出由IP(3)R2介导的更大的钙信号，而这种类型的钙信号的缺失降低了癫痫持续状态后的癫痫敏感性。立即但不迟于药物抑制小胶质细胞的激活，可阻止随后的反应性星形胶质细胞、异常的星形胶质细胞钙信号和增强的癫痫敏感性。这些发现表明，神经胶质细胞的顺序激活构成了癫痫持续状态后癫痫发生的原因之一。因此，我们的研究结果表明，预防癫痫持续状态后癫痫的治疗靶点应从小胶质细胞(早期)转移到星形胶质细胞(晚期)。
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 Ca2+ signals mediated by IP(3)R2, 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 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).