{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:59:56Z","timestamp":1782316796066,"version":"3.54.5"},"reference-count":138,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hungarian Brain Research Program","award":["NAP2022-I-1\/2022"],"award-info":[{"award-number":["NAP2022-I-1\/2022"]}]},{"name":"Hungarian Brain Research Program","award":["RRF-2.3.1-21-2022-00011"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00011"]}]},{"name":"Programme Sz\u00e9chenyi Plan Plus","award":["NAP2022-I-1\/2022"],"award-info":[{"award-number":["NAP2022-I-1\/2022"]}]},{"name":"Programme Sz\u00e9chenyi Plan Plus","award":["RRF-2.3.1-21-2022-00011"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Early-life stress may increase the risk of neuropsychiatric disorders via immune activation. While the purinergic signaling pathway is implicated in psychiatric disorders, the specific role of the P2X7 receptor (P2X7R) in anxiety, depression, and childhood trauma still requires further clarification. Upon chronic stress, excessive ATP release activates purinergic P2X7R signalling in the brain contributing to long-lasting neuroinflammation, which potentially promotes the development of psychiatric disorders. There is also a putative link between the P2X7 receptor gene, located on chromosome 12q24, and the development of anxiety and depression. This review aims to systematically examine how P2X7R contributes to the pathophysiology of anxiety and depressive disorders, with a particular focus on early-life stress (ELS). It offers a comprehensive synthesis of the current findings, emphasizing the previously unexplored intersections between P2X7R signaling, early-life stress, and psychiatric disorders. These interactions may shape long-term neuroinflammation, contributing to the development of anxiety and depression, and offer new insights into potential therapeutic targets. The review integrates the role of P2X7R regarding both indirect mechanisms\u2014such as the modulation and long-term transmission of neuroinflammation following environmental stressors and vulnerability\u2014and direct genetic associations with psychiatric conditions, including the influence of single-nucleotide polymorphisms (SNPs), haplotypes, and other variants within the P2X7 gene. Special emphasis is placed on the impact of early-life stress, drawing primarily on preclinical findings to elucidate underlying mechanisms.<\/jats:p>","DOI":"10.3390\/ijms26104687","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T10:27:41Z","timestamp":1747218461000},"page":"4687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["From Childhood Woes to Adult Blues: Unmasking the Role of Early Traumas, P2X7 Receptor, and Neuroinflammation in Anxiety and Depression"],"prefix":"10.3390","volume":"26","author":[{"given":"Zsuliet","family":"Kristof","sequence":"first","affiliation":[{"name":"Discipline of Psychiatry, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8301-6299","authenticated-orcid":false,"given":"Dorottya","family":"Szabo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, HUN-REN Institute of Experimental Medicine, 1083 Budapest, Hungary"},{"name":"Janos Szentagothai Doctoral School, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Sperlagh","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, HUN-REN Institute of Experimental Medicine, 1083 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora","family":"Torok","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Semmelweis University, 1089 Budapest, Hungary"},{"name":"Center of Pharmacology and Drug Research & Development, Semmelweis University, 1089 Budapest, Hungary"},{"name":"Hungarian Brain Research Program, NAP3.0-SE Neuropsychopharmacology Research Group, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9015-4203","authenticated-orcid":false,"given":"Xenia","family":"Gonda","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Semmelweis University, 1089 Budapest, Hungary"},{"name":"Center of Pharmacology and Drug Research & Development, Semmelweis University, 1089 Budapest, Hungary"},{"name":"Hungarian Brain Research Program, NAP3.0-SE Neuropsychopharmacology Research Group, 1089 Budapest, Hungary"},{"name":"Department of Psychiatry and Psychotherapy, Semmelweis University, 1082 Budapest, Hungary"},{"name":"Department of Clinical Psychology, Semmelweis University, 1092 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/7854_2019_89","article-title":"Early-Life Adversity, Systemic Inflammation and Comorbid Physical and Psychiatric Illnesses of Adult Life","volume":"44","author":"Nettis","year":"2020","journal-title":"Curr. 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