P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder

Sarah Bou Sader Nehme; Sandra Sanchez-Sarasua; Ramy Adel; Marie Tuifua; Awatef Ali; Amina E Essawy; Sherine Abdel Salam; Walid Hleihel; Eric Boué-Grabot; Marc Landry

doi:10.3389/fphar.2023.1288994

P2X4 signalling contributes to hyperactivity but not pain sensitization comorbidity in a mouse model of attention deficit/hyperactivity disorder

Front Pharmacol. 2024 Jan 4:14:1288994. doi: 10.3389/fphar.2023.1288994. eCollection 2023.

Authors

Sarah Bou Sader Nehme^#^{1

2}, Sandra Sanchez-Sarasua^#^{1

3}, Ramy Adel⁴, Marie Tuifua¹, Awatef Ali⁴, Amina E Essawy⁴, Sherine Abdel Salam⁴, Walid Hleihel², Eric Boué-Grabot¹, Marc Landry¹

Affiliations

¹ University of Bordeaux, CNRS, Institute of Neurodegenerative Diseases, IMN, UMR 5293, Bordeaux, France.
² Department of Biology, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh, Lebanon.
³ Faculty of Health Sciences, University of Jaume I, Castellon, Spain.
⁴ Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt.

^# Contributed equally.

Abstract

Introduction: Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by hyperactivity, inattention, and impulsivity that often persist until adulthood. Frequent comorbid disorders accompany ADHD and two thirds of children diagnosed with ADHD also suffer from behavioural disorders and from alteration of sensory processing. We recently characterized the comorbidity between ADHD-like symptoms and pain sensitisation in a pharmacological mouse model of ADHD, and we demonstrated the implication of the anterior cingulate cortex and posterior insula. However, few studies have explored the causal mechanisms underlying the interactions between ADHD and pain. The implication of inflammatory mechanisms has been suggested but the signalling pathways involved have not been explored. Methods: We investigated the roles of purinergic signalling, at the crossroad of pain and neuroinflammatory pathways, by using a transgenic mouse line that carries a total deletion of the P2X4 receptor. Results: We demonstrated that P2X4 deletion prevents hyperactivity in the mouse model of ADHD. In contrast, the absence of P2X4 lowered thermal pain thresholds in sham conditions and did not affect pain sensitization in ADHD-like conditions. We further analysed microglia reactivity and the expression of inflammatory markers in wild type and P2X4KO mice. Our results revealed that P2X4 deletion limits microglia reactivity but at the same time exerts proinflammatory effects in the anterior cingulate cortex and posterior insula. Conclusion: This dual role of P2X4 could be responsible for the differential effects noted on ADHD-like symptoms and pain sensitization and calls for further studies to investigate the therapeutic benefit of targeting the P2X4 receptor in ADHD patients.

Keywords: P2X4; anterior cingulate cortex; attention deficit/hyperactivity disorders; pain sensitization; posterior insula; purines.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. SS was supported by the SAFAR doctoral scholarship (111751P and 129650N) funded by the Embassy of France in Lebanon and by a grant from the Conseil Régional de Nouvelle Aquitaine (AAPR2021A-2020-12051410). SS-S was supported by the Margarita Salas postdoctoral contract MGS/2021/33 (UP2021-021) financed by the European Union-NextGenerationEU. This work was supported by grants from ANR (ANR-20-CE14-0016), the ‘Fédération pour la Recherche sur le Cerveau’ (FRC), and the French government in the framework of the University of Bordeaux’s IdEx “Investments for the Future” program/GPR BRAIN_2030.