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CX3CL1/CX3CR1-dependent microglial phagocytosis of oligodendrocyte precursor cells contributes to sevoflurane-induced myelination impairments in neonatal mice
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DOI：10.1186/s12974-026-03997-8.png)
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Abstract
En 中文
General anesthesia exposure in early life may disrupt the normal progression of developmental myelination, but the underlying mechanisms remain unclear. Early postnatal microglia in developing white matter exhibit diverse transcriptional and functional states, including a population with pronounced phagocytic activity. This study aims to investigate whether sevoflurane impairs oligodendrocyte myelination by promoting microglial phagocytosis of oligodendrocyte precursor cells (OPCs). Mice received either a single 2-h exposure to 3.3% sevoflurane on postnatal day 2 (P2) or repeated 2-h exposures on P2, P3, and P4. Neurobehavioral tests were used to assess cognitive and fine motor functions. The effects of microglial phagocytosis of OPCs on cerebral myelination were assessed using three-dimensional reconstruction and related biochemical analysis. Our findings indicate that repeated sevoflurane exposure, rather than a single exposure, induced hypomyelination and was associated with persistent cognitive and fine motor deficits. Repeated sevoflurane exposures promoted microglial activation and excessive phagocytosis of OPCs, thereby decreasing the number of oligodendrocytes and impairing developmental myelination. Mechanistically, repeated sevoflurane exposure enhanced CX3CL1/CX3CR1 signaling in neonatal brain tissue. In cultured microglial cells, sevoflurane altered Rac1-related cytoskeletal regulation and increased phagocytic activity. CX3CR1 knockout attenuated the phagocytic ability of microglia and rescued oligodendrocyte myelination and neurobehaviors. This study indicates that CX3CL1/CX3CR1-dependent microglial phagocytosis of OPCs might contribute to sevoflurane-induced myelination impairments in neonatal mice, and provides a potential therapeutic target for preventing anesthesia-induced developmental neurotoxicity.
Keywords:
Sevoflurane
Developmental neurotoxicity
Microglia
Oligodendrocyte precursor cell
CX3CL1
CX3CR1
Rac1
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