Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis | Zendy

Xiuxiu Liu | Zendy; Lin Yang | Zendy; Ling-Xiao Shao | Zendy; Yang He | Zendy; Gang Wu | Zendy; Yu-huan Bao | Zendy; Nannan Lu | Zendy; DongMei Gong | Zendy; Ya-Ping Lu | Zendy; Tiantian Cui | Zendy; Ninghe Sun | Zendy; Danyang Chen | Zendy; WeiXing Shi | Zendy; Kohji Fukunaga | Zendy; Hongshan Chen | Zendy; Zhong Chen | Zendy; Feng Han | Zendy; YingMei Lu | Zendy

Open Access

Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis

Author(s) -

Xiuxiu Liu,

Lin Yang,

Ling-Xiao Shao,

Yang He,

Gang Wu,

Yu-huan Bao,

Nannan Lu,

DongMei Gong,

Ya-Ping Lu,

Tiantian Cui,

Ninghe Sun,

Danyang Chen,

WeiXing Shi,

Kohji Fukunaga,

Hongshan Chen,

Zhong Chen,

Feng Han,

YingMei Lu

Publication year - 2019

Publication title -

the journal of experimental medicine

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 8.483

H-Index - 448

eISSN - 1540-9538

pISSN - 0022-1007

DOI - 10.1084/jem.20180992

Subject(s) - epileptogenesis , cxc chemokine receptors , astrogliosis , cxcl1 , epilepsy , conditional gene knockout , knockout mouse , glutamate receptor , chemokine receptor , chemistry , pharmacology , neuroscience , microbiology and biotechnology , biology , chemokine , receptor , phenotype , biochemistry , central nervous system , gene

Blood-brain barrier (BBB) dysfunction has been suggested to play an important role in epilepsy. However, the mechanism mediating the transition from cerebrovascular damage to epilepsy remains unknown. Here, we report that endothelial cyclin-dependent kinase 5 (CDK5) is a central regulator of neuronal excitability. Endothelial-specific Cdk5 knockout led to spontaneous seizures in mice. Knockout mice showed increased endothelial chemokine (C-X-C motif) ligand 1 (Cxcl1) expression, decreased astrocytic glutamate reuptake through the glutamate transporter 1 (GLT1), and increased glutamate synaptic function. Ceftriaxone restored astrocytic GLT1 function and inhibited seizures in endothelial Cdk5-deficient mice, and these effects were also reversed after silencing Cxcl1 in endothelial cells and its receptor chemokine (C-X-C motif) receptor 2 (Cxcr2) in astrocytes, respectively, in the CA1 by AAV transfection. These results reveal a previously unknown link between cerebrovascular factors and epileptogenesis and provide a rationale for targeting endothelial signaling as a potential treatment for epilepsy.

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