From Childhood Woes to Adult Blues: Unmasking the Role of Early Traumas, P2X7 Receptor, and Neuroinflammation in Anxiety and Depression

Kristóf, Zsüliet and Szabó, Dorottya and Sperlágh, Beáta and Török, Dóra and Gonda, Xénia (2025) From Childhood Woes to Adult Blues: Unmasking the Role of Early Traumas, P2X7 Receptor, and Neuroinflammation in Anxiety and Depression. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 26 (10). No. 4687. ISSN 1661-6596

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Abstract

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—such as the modulation and long-term transmission of neuroinflammation following environmental stressors and vulnerability—and 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.

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