title: Wnt/β-catenin signaling mediates the seizure-facilitating effect of postischemic reactive astrocytes after pentylenetetrazole-kindling.
abstract: 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.
authors.affiliation: Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.|Department of Neurobiology and Collaborative Innovation Center for Brain Science, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Jialei
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Neurology, Anning Branch of Lanzhou General Hospital of Lanzhou Military Region, Lanzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Xunyuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yuanhang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai, China.|Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Institute of Developmental and Regenerative Biology, Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life Sciences, Hangzhou Normal University, Hangzhou, China.
authors.forename: Mengsheng
authors.initials: M
authors.lastname: Qiu
authors.affiliation: Department of Neurobiology and Collaborative Innovation Center for Brain Science, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Ya-Zhou
authors.initials: YZ
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D051176:beta Catenin; D010433:Pentylenetetrazole
keywords: Wnt/β-catenin signaling; ischemia; reactive astrocytes; seizure susceptibility