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The P2X7 receptor contributes to seizures and inflammation-driven long-lasting brain hyperexcitability following neonatal hypoxia in mice
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  • Jonathon Smith,
  • Aida Menendez Mendez,
  • Mariana Alves,
  • Alberto Parras,
  • Giorgia Conte,
  • Anindya Bhattacharya,
  • Marc Ceusters,
  • Annette Nicke,
  • David Henshall,
  • Eva Jimenez-Mateos,
  • Tobias Engel
Jonathon Smith
Royal College of Surgeons in Ireland

Corresponding Author:[email protected]

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Aida Menendez Mendez
Royal College of Surgeons in Ireland
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Mariana Alves
Royal College of Surgeons in Ireland
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Alberto Parras
University of Lausanne
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Giorgia Conte
Royal College of Surgeons in Ireland
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Anindya Bhattacharya
Janssen Research & Development, LLC.
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Marc Ceusters
Janssen Research and Development Belgium
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Annette Nicke
LMU Munich, Faculty of Medicine
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David Henshall
Royal College of Surgeons in Ireland
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Eva Jimenez-Mateos
Trinity College Dublin School of Medicine
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Tobias Engel
Royal College of Surgeons in Ireland
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Background and Purpose Neonatal seizures are a clinical emergency. Current anti-seizure medications, however, fail to resolve seizures in ~50% of infants. The P2X7 receptor (P2X7R) is an important driver of inflammation and evidence suggest P2X7R contributing to seizures and epilepsy in adults. To date, however, no genetic proof has been provided to determine the contribution of the P2X7R to neonatal seizures, its effects on inflammatory signalling during neonatal seizures and the therapeutic potential of P2X7R-based treatments on long-lasting brain excitability. Experimental Approach Neonatal seizures were induced via global hypoxia in 7 day-old mouse pups (P7). The role of P2X7Rs during seizures was analyzed in P2X7R overexpressing and knock-out mice. Treatment of wild-type mice post-hypoxia with the P2X7R antagonist JNJ-47965567 was used to determine the effects of the P2X7R on long-lasting brain hyperexcitability. Cell type-specific P2X7R expression was analyzed via P2X7R-EGFP reporter mice. RNA sequencing was used to monitor P2X7R-dependent hippocampal down-stream signalling. Key Results P2X7R deletion reduced seizure severity whereas P2X7R overexpression exacerbated seizure severity and reduced responsiveness to anti-seizure medication. P2X7R deficiency let to an anti-inflammatory phenotype in microglia and treatment of mice with a P2X7R antagonist reduced long-lasting brain hyperexcitability. RNA sequencing identified several pathways altered in P2X7R knock-out mice after neonatal hypoxia including a down-regulation of genes implicated in inflammation and glutamatergic signalling. Conclusion and Implications Treatments based on targeting the P2X7R may represent a novel therapeutic strategy for neonatal seizures with P2X7Rs contributing to the generation of neonatal seizures, driving inflammatory processes and long-term hyperexcitability states.
02 Oct 2022Submitted to British Journal of Pharmacology
06 Oct 2022Submission Checks Completed
06 Oct 2022Assigned to Editor
10 Oct 2022Reviewer(s) Assigned
31 Oct 2022Review(s) Completed, Editorial Evaluation Pending
05 Nov 2022Editorial Decision: Revise Minor
13 Dec 20221st Revision Received
15 Dec 2022Submission Checks Completed
15 Dec 2022Assigned to Editor
15 Dec 2022Review(s) Completed, Editorial Evaluation Pending
19 Dec 2022Reviewer(s) Assigned
31 Dec 2022Editorial Decision: Accept