Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Chris Greene, Nicole Hanley, Cristina R. Reschke, Avril Reddy, Maarja A. Mäe, Ruairi Connolly, Claire Behan, Eoin O’Keeffe, Isobel Bolger, Natalie Hudson, Conor Delaney, Michael A. Farrell, Donncha F. O’Brien, Jane Cryan, Francesca M. Brett, Alan Beausang, Christer Betsholtz, David C. Henshall, Colin P. Doherty and Matthew Campbell ()
Additional contact information
Chris Greene: Smurfit Institute of Genetics, Trinity College Dublin
Nicole Hanley: Smurfit Institute of Genetics, Trinity College Dublin
Cristina R. Reschke: University of Medicine and Health Sciences
Avril Reddy: Smurfit Institute of Genetics, Trinity College Dublin
Maarja A. Mäe: Uppsala University
Ruairi Connolly: University of Medicine and Health Sciences
Claire Behan: University of Medicine and Health Sciences
Eoin O’Keeffe: Smurfit Institute of Genetics, Trinity College Dublin
Isobel Bolger: Smurfit Institute of Genetics, Trinity College Dublin
Natalie Hudson: Smurfit Institute of Genetics, Trinity College Dublin
Conor Delaney: Smurfit Institute of Genetics, Trinity College Dublin
Michael A. Farrell: Beaumont Hospital
Donncha F. O’Brien: Beaumont Hospital
Jane Cryan: Beaumont Hospital
Francesca M. Brett: Beaumont Hospital
Alan Beausang: Beaumont Hospital
Christer Betsholtz: Uppsala University
David C. Henshall: University of Medicine and Health Sciences
Colin P. Doherty: University of Medicine and Health Sciences
Matthew Campbell: Smurfit Institute of Genetics, Trinity College Dublin

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.

Date: 2022
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DOI: 10.1038/s41467-022-29657-y

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