Repeated neonatal sevoflurane exposure causes adolescent anxiety/depression via microglial P2Y12R-Wnt/β-catenin pathway-mediated neurogenesis deficits

Sevoflurane is the most commonly used inhaled anesthetic in pediatric and obstetric practice. However, early-life multiple sevoflurane exposure may increase long-term neurodevelopmental risks, though the underlying mechanisms remain incompletely understood. This study aimed to elucidate the role of the microglia-specific purinergic receptor P2Y12R in early-life multiple sevoflurane-induced developmental neurotoxicity. Using a neonatal mouse model of repeated sevoflurane exposure combined with behavioral tests, immunofluorescence staining, Western blot, qRT‑PCR, and microglia-specific conditional P2Y12R knockout, we found that early-life multiple sevoflurane exposures induce anxiety- and depression-like behaviors in adolescent mice, accompanied by impaired hippocampal neurogenesis and upregulated microglial P2Y12R expression. Mechanistically, sevoflurane upregulates microglial P2Y12R, which suppresses the activity of the Wnt/β‑catenin signaling pathway in newborn neurons, thereby impairing neurogenesis. Both genetic ablation of microglial P2Y12R and pharmacological activation of the Wnt/β‑catenin pathway reversed these abnormalities. Our study delineates a previously unrecognized signaling axis‑microglial P2Y12R‑Wnt/β‑catenin‑that underlies sevoflurane-induced impairment of hippocampal neurogenesis and adolescent emotional dysfunction. These findings have important implications for pediatric anesthesia safety and identify the microglial P2Y12R-Wnt/β-catenin axis as a potential therapeutic target for preventing anesthesia-related neurodevelopmental risks in young children.