Neonatal Sevoflurane Exposure Exerts Sex-Specific Effects on Cognitive Function via C3- and TLR4-Related M1/M2 Microglial Cell Polarisation in Rats

Abstract

In this study, we aimed to explore the sex-specific effects and mechanisms of sevoflurane exposure on the neural development of pubertal rats on the basis of M1/M2 microglial cell polarisation and related signalling pathways. A total of 48 rat pups (24 males and 24 females) were assigned to the 0- or 2-h sevoflurane exposure group on the seventh day after birth. The Morris water maze (MWM) test was subsequently conducted on the 32nd to 38th days after birth. M1/M2 microglial cell polarisation, C3 and TLR4 expression, and synapse growth were analysed within specific brain zones by immunofluorescence after the MWM test. We found that the negative effects caused by sevoflurane exposure were weaker in female rats than in male rats and had less influence on spatial memory. Sevoflurane exposure has opposite effects on microglial M1 polarisation in the different sexes but can promote M2 polarisation, with more obvious effects seen in female rats. In addition, sevoflurane exposure had bidirectional effects on C3 expression in different zones, while it clearly downregulated C3 expression in female rats. Moreover, sevoflurane decreased TLR4 expression in the hippocampus, whereas female rats exhibited better resistance, especially in the dentate gyrus. Compared with male rats, female rats were more resistant to the synaptic reduction effect of sevoflurane exposure. In conclusion, we found that neonatal sevoflurane exposure could exhibit sex-specific effects via the regulation of C3- and TLR4-related microglial cell polarisation. In addition, subregional regulation in the hippocampus might also contribute to its sex-specific effects.