Sevoflurane-induced disruption of critical period Arc signaling drives aberrant microglial synaptic pruning and cognitive deficits.

Summary

In rodent models, early-life sevoflurane activated GSK3β, suppressed critical-period Arc upregulation, and derailed microglial synaptic pruning, leading to later synaptic loss and cognitive deficits. Transient Arc knockdown phenocopied these effects, while critical-period restoration of Arc via a Dox-inducible system normalized pruning trajectories and prevented long-term cognitive impairment.

Key Findings

• The first three postnatal weeks constitute a critical vulnerability window to sevoflurane.
• Sevoflurane activated GSK3β and reduced Arc during the critical period, disrupting microglial synaptic pruning.
• Arc antisense knockdown recapitulated sevoflurane-induced pruning defects and later cognitive deficits.
• Critical-period Arc restoration via a Dox-inducible system prevented aberrant pruning and long-term cognitive impairment.

Clinical Implications

While preclinical, the work highlights Arc stabilization and modulation of GSK3β as candidate neuroprotective strategies and emphasizes timing as critical in mitigating anesthetic developmental neurotoxicity.

Limitations

• Preclinical rodent models may not fully recapitulate human anesthetic exposures and developmental timelines.
• Specific exposure paradigms and potential sex/species differences require further validation for clinical translation.

Future Directions

Test Arc-stabilizing or GSK3β-modulating agents in translational models, define human-equivalent critical windows, and develop perioperative neuroprotection protocols for pediatric anesthesia.