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However, current anti\u2010seizure medications fail to resolve seizures in ~50% of infants. The P2X7 receptor (P2X7R) is an important driver of inflammation, and evidence suggests that P2X7R contributes to seizures and epilepsy in adults. However, no genetic proof has yet been provided to determine what contribution P2X7R makes to neonatal seizures, its effects on inflammatory signalling during neonatal seizures, and the therapeutic potential of P2X7R\u2010based treatments on long\u2010lasting brain excitability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Neonatal seizures were induced by global hypoxia in 7\u2010day\u2010old mouse pups (P7). The role of P2X7Rs during seizures was analysed in P2X7R\u2010overexpressing and knockout mice. Treatment of wild\u2010type mice after hypoxia with the P2X7R antagonist JNJ\u201047965567 was used to determine the effects of the P2X7R on long\u2010lasting brain hyperexcitability. Cell type\u2010specific P2X7R expression was analysed in P2X7R\u2010EGFP reporter mice. RNA sequencing was used to monitor P2X7R\u2010dependent hippocampal downstream signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>P2X7R deletion reduced seizure severity, whereas P2X7R overexpression exacerbated seizure severity and reduced responsiveness to anti\u2010seizure medication. P2X7R deficiency led to an anti\u2010inflammatory phenotype in microglia, and treatment of mice with a P2X7R antagonist reduced long\u2010lasting brain hyperexcitability. RNA sequencing identified several pathways altered in P2X7R knockout mice after neonatal hypoxia, including a down\u2010regulation of genes implicated in inflammation and glutamatergic signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>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\u2010term hyperexcitability states.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16033","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T15:59:29Z","timestamp":1673625569000},"page":"1710-1729","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The P2X7 receptor contributes to seizures and inflammation\u2010driven long\u2010lasting brain hyperexcitability following hypoxia in neonatal mice"],"prefix":"10.1111","volume":"180","author":[{"given":"Jonathon","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Physiology and Medical Physics RCSI University of Medicine and Health Sciences  Dublin Ireland"},{"name":"FutureNeuro, SFI Research Centre for Chronic and Rare Neurological Diseases RCSI University of Medicine and Health Sciences  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Men\u00e9ndez M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics RCSI University of Medicine and Health Sciences  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics RCSI University of Medicine and Health Sciences  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Parras","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Biology and Medicine University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Conte","sequence":"additional","affiliation":[{"name":"Department of Physiology and Medical Physics RCSI University of Medicine and Health Sciences  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anindya","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Neuroimmunology Discover, Neuroscience Janssen R&amp;D  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ceusters","sequence":"additional","affiliation":[{"name":"Neuroscience Therapeutic Area, Janssen Research and Development Janssen Pharmaceutica NV  Beerse Belgium"},{"name":"The Marc 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