Wnt/β‐catenin signaling mediates the seizure‐facilitating effect of postischemic reactive astrocytes after pentylenetetrazole‐kindling
Wnt/β‐catenin signaling mediates the seizure‐facilitating effect of postischemic reactive astrocytes after pentylenetetrazole‐kindling
复制标题
DOI：
10.1002/glia.22984
复制
发表时间：
2016-03
期刊：
影响因子：
6.2
通讯作者：
Jialei Yang;Xiufen Zhang;Yin Wu;Bo Zhao;Xunyuan Liu;Yuanhang Pan;Yonghong Liu;Yu-Qiang Ding;M. Qiu;Ya-zhou Wang;Gang Zhao
中科院分区：
文献类型：
--
作者：
Jialei Yang;Xiufen Zhang;Yin Wu;Bo Zhao;Xunyuan Liu;Yuanhang Pan;Yonghong Liu;Yu-Qiang Ding;M. Qiu;Ya-zhou Wang;Gang Zhao
缺血不仅导致组织损伤，而且诱发癫痫发作，这反过来又使缺血的结果恶化。最近的研究表明，反应性星形胶质细胞的稳态功能受损，这被认为是促进癫痫发作的发展。然而，这种反应性星形胶质细胞的表型是如何调节的仍不清楚。在这里，我们使用戊四氮（PTZ）点燃模型，研究了反应性星形胶质细胞及其细胞内Wnt/β-连环蛋白信号传导在缺血增加癫痫发作易感性中的作用。我们的数据表明，体感皮层缺血显著增加了PTZ诱导癫痫发作的易感性。Nestin阳性反应性星形胶质细胞的基因消融显著降低了癫痫发作的发生率和严重程度。通过使用Wnt信号报告小鼠系Topgal小鼠，我们发现缺血后反应性星形胶质细胞中的Wnt/β-catenin信号上调。反应性星形胶质细胞中β-catenin的耗竭显著降低了癫痫发作的易感性和缺血皮质中PTZ诱导的c-Fos表达。相反，β-catenin在反应性星形胶质细胞中的过表达显著增加了癫痫发作的易感性和c-Fos的表达。此外，水通道蛋白-4（AQP-4）和内向整流K+通道4.1（Kir4.1）的表达（据报道与癫痫发作相关的两种分子）在β-连环蛋白缺失或过表达的反应性星形胶质细胞中受到相反的影响。总之，这些数据表明星形胶质细胞Wnt/β-连环蛋白信号转导至少部分地解释了缺血增加的癫痫易感性。抑制Wnt/β-catenin信号传导可能在未来用于预防缺血后癫痫发作。GLIA 2016;64：1083-1091
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