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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Author

Listed:
  • 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
    RCSI 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
    Health Care Centre, Hospital 5, St James’s Hospital
    Academic Unit of Neurology, Room 5.41, Biomedical Sciences Institute, Trinity College Dublin)

  • Claire Behan

    (University of Medicine and Health Sciences
    Health Care Centre, Hospital 5, St James’s Hospital
    Academic Unit of Neurology, Room 5.41, Biomedical Sciences Institute, Trinity College Dublin)

  • 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
    RCSI University of Medicine and Health Sciences)

  • Colin P. Doherty

    (University of Medicine and Health Sciences
    Health Care Centre, Hospital 5, St James’s Hospital
    Academic Unit of Neurology, Room 5.41, Biomedical Sciences Institute, Trinity College Dublin)

  • Matthew Campbell

    (Smurfit Institute of Genetics, Trinity College Dublin
    University of Medicine and Health Sciences)

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.

Suggested Citation

  • 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 , 2022. "Microvascular stabilization via blood-brain barrier regulation prevents seizure activity," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29657-y
    DOI: 10.1038/s41467-022-29657-y
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    References listed on IDEAS

    as
    1. Michael Vanlandewijck & Liqun He & Maarja Andaloussi Mäe & Johanna Andrae & Koji Ando & Francesca Gaudio & Khayrun Nahar & Thibaud Lebouvier & Bàrbara Laviña & Leonor Gouveia & Ying Sun & Elisabeth Ra, 2018. "Author Correction: A molecular atlas of cell types and zonation in the brain vasculature," Nature, Nature, vol. 560(7716), pages 3-3, August.
    2. Naoki Honkura & Mark Richards & Bàrbara Laviña & Miguel Sáinz-Jaspeado & Christer Betsholtz & Lena Claesson-Welsh, 2018. "Intravital imaging-based analysis tools for vessel identification and assessment of concurrent dynamic vascular events," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. Michael Vanlandewijck & Liqun He & Maarja Andaloussi Mäe & Johanna Andrae & Koji Ando & Francesca Del Gaudio & Khayrun Nahar & Thibaud Lebouvier & Bàrbara Laviña & Leonor Gouveia & Ying Sun & Elisabet, 2018. "A molecular atlas of cell types and zonation in the brain vasculature," Nature, Nature, vol. 554(7693), pages 475-480, February.
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