Synaptotagmin III Plays a Protective Role in Neonatal Multiple Sevoflurane Exposure-Induced Cognitive Deficits in Mice

General anesthesia in infants and young children raises concerns about potential neurodevelopmental effects, as anesthetics such as sevoflurane may impair cognitive function and increase neuroinflammation. Synaptotagmin 3 (Syt3), a protein involved in synaptic regulation, has been identified as a possible modulator of these effects. This study explores the role of Syt3 in mitigating cognitive and inflammatory outcomes following neonatal sevoflurane exposure in mice. To this end, neonatal wild-type (WT) and Syt3 knockout (Syt3^–/–) C57BL/6 mice were exposed to 3% sevoflurane for 2 h daily on postnatal days 7–9. Syt3 protein levels in the hippocampus were measured postexposure using Western blot and ELISA. Neuroinflammatory markers (IL-1β, TNF-α, and MCP-1) were quantified by ELISA, and cognitive function was assessed using object location memory and novel object recognition tasks. Anxiety-like behavior was evaluated with the elevated plus maze. Syt3 overexpression was achieved in WT mice by using CRISPR activation plasmids. Our results indicated that sevoflurane exposure reduced Syt3 levels in the hippocampus of WT mice, correlated with heightened neuroinflammation and cognitive deficits. Syt3^–/– mice exhibited exacerbated cognitive impairment, increased inflammation, and more severe anxiety-like behavior. Overexpression of Syt3 in WT mice mitigated these effects, improving cognitive function, reducing inflammation, and alleviating anxiety-like behavior. Syt3 protects against sevoflurane-induced cognitive and inflammatory impairments in neonatal mice. These findings suggest Syt3 as a potential therapeutic target for reducing neurodevelopmental risks associated with pediatric anesthesia.