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

Dan-Yang Chen,Dong-Mei Gong,Feng Han,Gang Wu,Hong-Shan Chen,Kohji Fukunaga,Lin Yang,Ling-Xiao Shao,Nan-Nan Lu,Ning-He Sun,Tian-Tian Cui,Wei-Xing Shi,Xiu-Xiu Liu,Ya-Ping Lu,Yang He,Ying-Mei Lu,Yu-Huan Bao,Zhong Chen

doi:10.1084/jem.20180992

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.

Highlights

Epilepsy, characterized by recurrent seizures, affects 65–70 million people worldwide (Mosheet al., 2015; Thijs et al, 2019)
The hyperexcitability underlying epilepsy is believed to be caused by an imbalance of synaptic excitation and inhibition (Li et al, 2011; Neumann et al, 2017; Paz and Huguenard, 2015), antiepileptic strategies directly targeting neuronal excitability have proven to be insufficient in a significant proportion of patients (Loscher and Schmidt, 2006; Eyo et al, 2017; Ferlazzo et al, 2017)
Endothelial conditional deletion of Cdk5 induces spontaneous seizures To investigate the role of endothelial Cdk5 in brain, we generated three sets of conditional endothelial-specific Cdk5 KO mice (Tan et al, 2019; Cdh5-Cre;Cdk5f/f mice, Cdh5-CreERT2;Cdk5f/f mice, BR1-iCre-Cdk5f/f mice; Fig. S1, A–E)

Summary

Introduction

Epilepsy, characterized by recurrent seizures, affects 65–70 million people worldwide (Mosheet al., 2015; Thijs et al, 2019). Whole-cell recordings in brain slices showed an increased excitability of hippocampal CA1 pyramidal neurons in Cdh5-Cre;Cdk5f/f mice.

Results

Conclusion