CX3CL1/CX3CR1-dependent microglial phagocytosis of oligodendrocyte precursor cells contributes to sevoflurane-induced myelination impairments in neonatal mice.

Summary

In neonatal mice, repeated but not single sevoflurane exposure caused hypomyelination and persistent cognitive and fine motor deficits. The study linked these effects to enhanced CX3CL1/CX3CR1 signaling, Rac1-related cytoskeletal changes, and excessive microglial phagocytosis of oligodendrocyte precursor cells; CX3CR1 knockout attenuated both cellular and behavioral abnormalities.

Key Findings

• Repeated 2-hour sevoflurane exposure on postnatal days 2–4, but not a single exposure, induced hypomyelination and persistent cognitive and fine motor deficits.
• Repeated exposure increased microglial activation and phagocytosis of oligodendrocyte precursor cells, reducing oligodendrocyte numbers.
• CX3CR1 knockout reduced microglial phagocytosis and rescued myelination and neurobehavioral abnormalities.

Clinical Implications

The results support caution regarding repeated early-life anesthesia exposure and may guide future studies of anesthesia strategies, neuroprotective interventions, and biomarkers of developmental neurotoxicity. They do not establish clinical harm in human infants or justify changing current anesthesia practice without clinical validation.

Limitations

• The findings derive from neonatal mice and may not translate directly to human infants.
• The study did not establish the exposure threshold, long-term adult outcomes, or the relevance of clinically diverse anesthesia regimens.

Future Directions

Future research should validate the pathway in human-relevant models, define exposure-response relationships, assess long-term neurodevelopmental outcomes, and test pharmacological or perioperative strategies that selectively modulate microglial phagocytosis without impairing normal immune functions.