Wnt/β-catenin signaling mediates the seizure-facilitating effect of postischemic reactive astrocytes after pentylenetetrazole-kindling

详细信息    查看全文

• 作者：Jialei Yang ; Xiufen Zhang ; Yin Wu ; Bo Zhao ; Xunyuan Liu ; Yuanhang Pan ; Yonghong Liu ; Yuqiang Ding ; Mengsheng Qiu ; Ya-Zhou Wang and Gang Zhao
• 关键词：reactive astrocytes ; Wnt/&beta ; -catenin signaling ; seizure susceptibility ; ischemia
• 刊名：Glia
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：64
• 期：6
• 页码：1083-1091
• 全文大小：915K
• ISSN：1098-1136

文摘

Ischemia not only leads to tissue damage, but also induces seizures, which in turn worsens the outcome of ischemia. Recent studies have revealed the impaired homeostatic functions of reactive astrocytes, which were thought to facilitate the development of seizures. However, how this phenotype of reactive astrocytes is regulated remains unclear. Here, using pentylenetetrazole (PTZ)-kindling model, we investigated the roles of reactive astrocytes and their intracellular Wnt/β-catenin signaling in the ischemia-increased seizure susceptibility. Our data showed that somatosensory cortical ischemia significantly increased the susceptibility to PTZ-induced seizure. Genetic ablation of Nestin-positive reactive astrocytes significantly decreased the incidence and severity of seizures. By using a Wnt signaling reporter mice line Topgal mice, we found that Wnt/β-catenin signaling was upregulated in reactive astrocytes after ischemia. Depletion of β-catenin in reactive astrocytes significantly decreased the susceptibility of seizures and the expression of c-Fos induced by PTZ in the ischemic cortex. Overexpression of β-catenin in reactive astrocytes, in contrast, significantly increased seizure susceptibility and the expression of c-Fos. Furthermore, the expression of aquaporin-4 (AQP-4) and inwardly rectifying K⁺ channel 4.1 (Kir4.1), two molecules reportedly associated with seizure development, was oppositely affected in reactive astrocytes with β-catenin depletion or overexpression. Taken together, these data indicated that astrocytic Wnt/β-catenin signaling accounts, at least partially, for the ischemia-increased seizure susceptibility. Inhibiting Wnt/β-catenin signaling may be utilized in the future for preventing postischemic seizures. GLIA 2016;64:1083–1091