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 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 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 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).
Highlights
Epileptogenesis, i.e., the process leading to epilepsy, is a common sequel of brain insults such as brain injury, cerebrovascular disease, or status epilepticus (SE; refs. 1, 2)
The area of Iba1+ microglia was significantly increased in CA1 on days 1–7 after SE, which was followed by an increase in the area of GFAP+ astrocytes in CA1 on days 3–28 after SE (Figure 1, C and E)
We demonstrate that SE induced sequential activation of glial cells, i.e., the initial activation of microglia, followed by astrocytic activation, which is essential for seizure susceptibility or epileptogenesis
Summary
Epileptogenesis, i.e., the process leading to epilepsy, is a common sequel of brain insults such as brain injury, cerebrovascular disease, or status epilepticus (SE; refs. 1, 2). Extensive activation of glial cells, including microglia and astrocytes, has been well documented during this latent period in various animal models of epilepsy [5,6,7]. The association of pathology with reactive glial cells is widely recognized, it is unclear whether such microglial and astrocytic activation constitutes primary causes of epilepsy or rather represents the results of repeated seizures. In chemoconvulsant-induced epilepsy models, microglia are activated and produce proinflammatory mediators immediately after seizure onset [8]. The extent of microglial activation correlates with the seizure frequency in human drug-resistant epilepsy [10]. Such microglial activation may not persist chronically. The activation of microglia is well characterized, it is unclear whether these activated microglia affect developing epileptogenic processes directly or through the modulation of other cells, such as subsequent astrocytic activation
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