Mitophagy impairment drives microglia activation and results in cognitive deficits in neonatal mice following sevoflurane exposure

Abstract

Sevoflurane exposure induces cognitive deficits in neonatal mice. Mitophagy was closely correlated to sevoflurane inhalation induced neurotoxicity in developing brains. However, the underlying mechanisms have not been fully elucidated. In this study, we attempted to clarify the role of mitophagy in neonatal mice undergoing sevoflurane exposure. BV2 microglial cells were cultured, and mcherry-EGFP-LC3B adenovirus were transfected. The results showed that the fluorescence intensity of GFP was markedly increased after sevoflurane exposure, and rapamycin administration could mitigate this effect. The mitophagy flux test showed that sevoflurane exposure reduced the degree of colocalization between Mito-Traker and Lyso-Traker fluorescent, while which was elevated by rapamycin treatment. The immunofluorescence assay suggested that sevoflurane inhalation resulted in the significant decrease of autolysosome formation, which was sharply enhanced in SEV group after rapamycin treatment. Meanwhile, sevoflurane inhalation shifted microglial M1/M2 phenotypic polarization, and rapamycin administration reversed this status. Moreover, the degree of colocalization among Iba-1, Synaptophysin (Syn) and lysosomal-associated membrane protein 1 (Lamp1) was increased after sevoflurane exposure, and that was reduced following rapamycin treatment. The behavioral performance was worse after sevoflurane inhalation in neonatal mice, and rapamycin treatment effectively improved the cognitive outcome. Collectively, these findings demonstrated that mitophagy impairment induced by sevoflurane exposure promoted microglia M1 phenotypic polarization and enlarged phagocytosis, and resulted in cognitive deficits, while rapamycin administration effectively reversed this tendency.