Microglia-mediated Perineuronal nets loss contributes to social memory deficit in male mice after repeated neonatal sevoflurane exposure.

BACKGROUND

Repeated early-life exposure to general anesthetics might affect social behavior. Perineuronal nets (PNNs), which enwrap around parvalbumin (PV) interneurons and support their function, are crucial for social memory. Given that microglia contribute to PNN remodeling and are responsive to anesthetic exposure, we hypothesized that repeated neonatal sevoflurane exposure impairs social memory via microglia-mediated PNN degradation.

METHODS

Mice were exposed to 2.5 % sevoflurane for 2 h daily during postnatal days 7-9. At postnatal day 28, we evaluated social behavior, PNN integrity, patch-clamp recordings, and conducted analyses of microglia and PV interneurons. Subsequently, we explored the effects of microglia depletion by PLX5622 (CSF1R antagonist) and repopulation on social behavior and PNNs after repeated sevoflurane exposure.

RESULTS

We found that repeated neonatal sevoflurane exposure led to social memory deficit in male mice. This deficit coincided with significant PNN loss in the prefrontal cortex, increased excitability of PV interneurons, and enhanced inhibitory input to pyramidal neurons. Microglia exhibited elevated phagocytic activity toward PNNs after repeated neonatal sevoflurane exposure. Notably, microglial depletion and repopulation rescued PNN integrity and social memory performance.

CONCLUSIONS

Our findings reveal microglia-dependent PNN degradation as a key mechanism underlying early-life sevoflurane exposure-induced social memory impairments in male mice. Targeting microglial activity or preserving PNNs may offer new strategies to prevent anesthesia-induced neurodevelopmental impairments.