Opposing effects of the purinergic P2X7 receptor on seizures in neurons and microglia in male mice
Alves, Mariana (RCSI University of Medicine & Health Sciences)
Gil, Beatriz (RCSI University of Medicine & Health Sciences)
Villegas-Salmerón, Javier (RCSI University of Medicine & Health Sciences)
Salari, Valentina (University of Verona)
Martins-Ferreira, Ricardo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Arribas Blázquez, Marina (Universidad Complutense de Madrid)
Menéndez Méndez, Aida (Universidad Europea de Madrid)
Da Rosa Gerbatin, Rogerio (RCSI University of Medicine and Health Sciences)
Smith, Jonathon (RCSI University of Medicine and Health Sciences)
de Diego-Garcia, Laura (RCSI University of Medicine & Health Sciences)
Conte, Giorgia (RCSI University of Medicine & Health Sciences)
Sierra-Marquez, Juan (Universidad Politécnica de Madrid)
Merino-Serrais, Paula (Universidad Politécnica de Madrid)
Mitra, Meghma (RCSI University of Medicine & Health Sciences)
Fernandez Martin, Ana (RCSI University of Medicine & Health Sciences)
Wang, Yitao (RCSI University of Medicine & Health Sciences)
Kesavan, Jaideep (RCSI University of Medicine & Health Sciences)
Melia, Ciara (RCSI University of Medicine & Health Sciences)
Parras, Alberto (RCSI University of Medicine & Health Sciences)
Beamer, Edward (Nottingham Trent University)
Zimmer, Béla (Ludwig-Maximilians-Universität München)
Heiland, Mona (RCSI University of Medicine & Health Sciences)
Cavanagh, Brenton (Royal College of Surgeons in Ireland)
Parcianello Cipolat, Rafael (RCSI University of Medicine & Health Sciences)
Morgan, James (University of Manchester)
Teng, Xinchen (Soochow University)
Prehn, Jochen H.M. (RCSI University of Medicine & Health Sciences)
Fabene, Paolo F (University of Verona)
Bertini, Giuseppe (University of Verona)
Artalejo, Antonio R. (Universidad Complutense de Madrid)
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Nicke, Annette (Ludwig-Maximilians-Universität München)
Olivos-Oré, Luis A. (Universidad Complutense de Madrid)
Connolly, Niamh M.C. (RCSI University of Medicine and Health Sciences)
Henshall, David C (RCSI University of Medicine and Health Sciences)
Engel, Tobias (RCSI University of Medicine & Health Sciences)

Data:	2024
Resum:	Background: The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood. Methods: Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter. Results: RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in experimental epilepsy. Finally, we show that viral transduction of P2X7R in GABAergic interneurons protects against evoked and spontaneous seizures in experimental temporal lobe epilepsy and in mice lacking Scn1a, a model of Dravet syndrome. Conclusions: Our results suggest a dual and opposing action of P2X7R in epilepsy and suggest P2X7R overexpression in GABAergic interneurons as a novel therapeutic strategy for acquired and, possibly, genetic forms of epilepsy.
Ajuts:	Agencia Estatal de Investigación PID2021-127924NB-I00 European Commission 796600 European Commission 766124
Nota:	Altres ajuts: Science Foundation Ireland (17/CDA/4708, SFI Centre for Research Training in Genòmics Data Science under Grant number 18/CRT/6214 and co-funded under the European Regional Development Fund and by FutureNeuro industry partners 16/RC/3948, 18/RI/5792, 21/RC/10294_P2); National Natural Science Foundation of China (31970550); Fondazione Cariverona -Bando Ricerca e Sviluppo 2022-ID52251-2022.0087
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	P2X7 receptor ; Status epilepticus ; Epilepsy ; Cell type-specific function
Publicat a:	Brain, behavior, and immunity, Vol. 120 (August 2024) , p. 121-140, ISSN 1090-2139

DOI: 10.1016/j.bbi.2024.05.023

20 p, 8.5 MB

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