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

Xiu xiu Liu, Lin Yang, Ling xiao Shao, Yang He, Gang Wu, Yu huan Bao, Nan nan Lu, Dong mei Gong, Ya ping Lu, Tian tian Cui, Ning he Sun, Dan yang Chen, Wei xing Shi, Kohji Fukunaga, Hong shan Chen, Zhong Chen, Feng Han, Ying mei Lu

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalJournal of Experimental Medicine
Volume217
Issue number1
DOIs
Publication statusPublished - 2020 Jan 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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