Endothelial Cdk5 deficit leads to the development of spontane

AAV-Cxcr2-RNAi was used to silence Cxcr2 in astrocytes and pyramidal neurons, AAV-shRNA was used to silence Cxcl1 expression in ECs in vivo. AAV-GLT1 was used to further test whether restoration of GLT1 function. (All viruses were packaged by BrainVTA)

The viruses used in this article from BrainVTA are in the table below

CRE Recombinase	PT-0220 rAAV-CaMKIIα-Cre-WPRE-pA PT-0209 rAAV-GFAP-Cre-WPRE-pA
Custom-Made AAVs	rAAV-U6-Loxp-CMV-mCherry-Loxp-shRNA AAV-Cxcr2-RNAi rAAV-Efla-DIO-GLT1-mCherry-WPRE-pA

Pub Date: 2019-11-07, DOI: 10.1084/jem.20180992 Email: sales@brainvta.com
Xiu-xiu Liu, Lin Yang, Ling-xiao Shao, Yang He, GangWu, Yu-huan Bao, Nan-nan Lu, Dong-mei Gong, Ya-ping Lu, Tian-tian Cui, Ning-he Sun, Dan-yangChen, Wei-xing Shi, Kohji Fukunaga, Hong-shan Chen, Zhong Chen, FengHan, and Ying-mei Lu

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.

Fig1. The expression of the chemokine CXCL1 is increased in Cdh5-Cre;Cdk5f/f mice.

To explore the mechanism mediating the transition from cerebrovascular damage to epilepsy, in the study, we found that endothelial-specific Cdk5 KO in mice induced spontaneous hippocampal epileptic discharges in an age-dependent manner. Our evidence further suggests that endothelial Cdk5 deletion down-regulates astrocytic GLT1-mediated current through endothelial chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine receptor 2 (CXCR2)-induced progressive reactive astrogliosis. The reduced GLT1 function increases glutamate synaptic current and may contribute to the development of epilepsy.

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