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Myelination Trajectory and Microglial Dynamics Following Repeated Sevoflurane Exposure in Developing Brain
Ji Che1, Yuanyuan Wu1, Jing Dong1
1Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, P. R. China.
Abstract:
The myelination is a critical process during brain development. This study aimed to explore the impact of volatile anesthetic sevoflurane on developing myelination and the role of microglial activation in this process. Neonatal C57BL/6J mice were exposed to sevoflurane at their postnatal 6-8 days. Neurobehavioral tests were used to assess fine motor and cognitive functions. Myelination of hippocampus (HC) and corpus callosum (CC), as well as microglial activation, were determined by western blotting and immunostaining. Lipid droplets were assessed by Oil-Red-O and Bodipy staining. Further, primary microglia were co-cultured with oligodendrocyte precursor cell (OPC) to determine the role of microglia in the proliferation and differentiation of OPC. And microglial inhibitor minocycline and CSF1R inhibitor PLX5622 were administered to assess the effects of microglial activation on developing myelination. The results showed that repeated sevoflurane exposure impaired both fine motor and cognitive functions and induced abnormal expressions of myelin-related proteins myelin basic protein (MBP) and platelet-derived growth factor α receptor (PDGFR-α). And accumulations of lipid droplets were found in the microglia of HC and CC after sevoflurane exposure. Further, the spatiotemporal response to repeated sevoflurane exposure in glial cells exhibited an aberrant myelination process and microglial polarization. The conditioned medium from sevoflurane-treated microglia inhibited the OPC proliferation and differentiation, while minocycline or PLX5622 alleviated sevoflurane-induced neuroinflammation and hypomyelination. Therefore, repeated sevoflurane exposure negatively affected OPC differentiation and myelination trajectory through hyperactivating microglia in developing brain, leading to motor and cognitive impairments, while microglial inhibition/depletion could protect against sevoflurane-induced damage on developing myelination.
Insights
Sevoflurane exposure in neonatal mice impairs brain development and motor skills by activating microglia, disrupting myelination. Inhibiting microglia protects against these harmful effects.
Area of Science:
- Neuroscience
- Developmental Biology
- Anesthesiology
Background:
- Myelination is crucial for proper brain development.
- Volatile anesthetics like sevoflurane may impact developing neural tissues.
- Microglial activation is implicated in neuroinflammation and developmental processes.
Purpose of the Study:
- To investigate the effects of sevoflurane on developing myelination in neonatal mice.
- To elucidate the role of microglial activation in sevoflurane-induced neurodevelopmental deficits.
- To assess the therapeutic potential of microglial inhibition against sevoflurane's adverse effects.
Main Methods:
- Neonatal mice exposed to sevoflurane; neurobehavioral tests performed.
- Western blotting and immunostaining used to assess myelination and microglial activation.
- In vitro co-culture of microglia and oligodendrocyte precursor cells (OPCs); pharmacological inhibition of microglia.
Main Results:
- Sevoflurane exposure impaired motor and cognitive functions, affecting myelin protein expression.
- Accumulation of lipid droplets observed in microglia; aberrant myelination and microglial polarization noted.
- Sevoflurane-induced microglial activation inhibited OPC proliferation and differentiation; microglial inhibitors showed protective effects.
Conclusions:
- Repeated sevoflurane exposure negatively impacts OPC differentiation and myelination via microglial hyperactivation.
- This leads to motor and cognitive impairments in the developing brain.
- Microglial inhibition offers a protective strategy against sevoflurane-induced developmental neurotoxicity.
