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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Greene, Chris, Hanley, Nicole, Reschke, Cristina R., Reddy, Avril, Mäe, Maarja A., Connolly, Ruairi, Behan, Claire, O’Keeffe, Eoin, Bolger, Isobel, Hudson, Natalie, Delaney, Conor, Farrell, Michael A., O’Brien, Donncha F., Cryan, Jane, Brett, Francesca M., Beausang, Alan, Betsholtz, Christer, Henshall, David C., Doherty, Colin P., Campbell, Matthew·2022·Nature Communications
DOI 10.1038/s41467-022-29657-yPMC PMC9010415
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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.

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Metadata

Authors
Greene, C., Hanley, N., Reschke, C. R., Reddy, A., Mäe, M. A., Connolly, R., Behan, C., O’Keeffe, E., Bolger, I., Hudson, N., Delaney, C., Farrell, M. A., O’Brien, D. F., Cryan, J., Brett, F. M., Beausang, A., Betsholtz, C., Henshall, D. C., Doherty, C. P., & Campbell, M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-04-14
Volume
13
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-022-29657-y
PMC
PMC9010415
Cited by
156
References
5
Language
en
Licence
Funders
Science Foundation Ireland (16/RC/3948)

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