The P2X7 receptor contributes to seizures and inflammation‐driven long‐lasting brain hyperexcitability following hypoxia in neonatal mice

Author:

Smith Jonathon12,Menéndez Méndez Aida1,Alves Mariana1,Parras Alberto3,Conte Giorgia1,Bhattacharya Anindya4,Ceusters Marc56,Nicke Annette7,Henshall David C.12,Jimenez‐Mateos Eva M.8,Engel Tobias12

Affiliation:

1. Department of Physiology and Medical Physics RCSI University of Medicine and Health Sciences Dublin Ireland

2. FutureNeuro, SFI Research Centre for Chronic and Rare Neurological Diseases RCSI University of Medicine and Health Sciences Dublin Ireland

3. Department of Biomedical Sciences, Faculty of Biology and Medicine University of Lausanne Lausanne Switzerland

4. Neuroimmunology Discover, Neuroscience Janssen R&D San Diego California USA

5. Neuroscience Therapeutic Area, Janssen Research and Development Janssen Pharmaceutica NV Beerse Belgium

6. The Marc Ceusters Company BV Diest Belgium

7. Walther Straub Institute of Pharmacology and Toxicology Ludwig Maximilian University of Munich Munich Germany

8. Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin The University of Dublin Dublin Ireland

Abstract

Background and PurposeNeonatal seizures represent a clinical emergency. However, current anti‐seizure 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‐based treatments on long‐lasting brain excitability.Experimental ApproachNeonatal seizures were induced by global hypoxia in 7‐day‐old mouse pups (P7). The role of P2X7Rs during seizures was analysed in P2X7R‐overexpressing and knockout mice. Treatment of wild‐type mice after 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 analysed in P2X7R‐EGFP reporter mice. RNA sequencing was used to monitor P2X7R‐dependent hippocampal downstream signalling.Key ResultsP2X7R deletion reduced seizure severity, whereas P2X7R overexpression exacerbated seizure severity and reduced responsiveness to anti‐seizure medication. P2X7R deficiency led 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 knockout mice after neonatal hypoxia, including a down‐regulation of genes implicated in inflammation and glutamatergic signalling.Conclusion and ImplicationsTreatments 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.

Funder

Deutsche Forschungsgemeinschaft

Science Foundation Ireland

H2020 Marie Skłodowska-Curie Actions

Irish Research Council for Science, Engineering and Technology

Publisher

Wiley

Subject

Pharmacology

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