<p>Sevoflurane, the primary anesthetic employed in pediatric populations, has been associated with neurotoxic effects in neonatal mice. However, the precise mechanisms underlying these effects remain to be fully elucidated. The present study utilizes single-nucleus RNA sequencing to investigate the impact of neonatal exposure to sevoflurane on the heterogeneity and intercellular communication of hippocampal astrocytes and neurons in neonatal mice. The results suggest that sevoflurane anesthesia leads to cognitive impairments, which are associated with a decreased population of neurons and astrocytes in the hippocampus of neonatal mice. The heightened activity of inflammatory and neurodevelopmental response pathways in the hippocampal astrocytes of mice displaying cognitive deficits, coupled with the enrichment of differentially expressed genes within neuronal subpopulations across various neurogenesis-related disorders, highlights the critical role of astrocytes in influencing neuronal function in the context of sevoflurane-induced neurotoxicity. Furthermore, our findings demonstrated that the interaction between astrocytes and neurons through NLGN1-NRXN1 inhibits the PI3K-Akt signaling pathway of neurons and contributes to the process of sevoflurane-induced neurotoxicity. In summary, our study identifies a novel intercellular communication mechanism in sevoflurane-induced cognitive impairment, providing insights into the molecular processes that could be targeted for therapeutic intervention.</p> Graphical Abstract <p> Single-nucleus RNA sequencing analysis revealed that repeated sevoflurane exposure disrupts the characteristic NRXN1-NLGN1 synaptic interaction between astrocytes and neurons, subsequently impairing the activation of PI3K/Akt signaling pathway and ultimately culminating in neurodevelopmental impairment in neonatal mice.</p> <p></p>