Neonatal Sevoflurane Exposure Induces Long-Term Cognitive Impairment via Epigenetically Mediated MMP9 Activation and Perineuronal Net Disruption in the Hippocampal CA2.

Summary

Repeated neonatal sevoflurane exposure produced persistent hippocampal CA2 perineuronal-net degradation and deficits in object recognition and social discrimination. The proposed mechanism links loss of H3K27me3 at the Mmp9 promoter to MMP9 activation, impaired BDNF/TrkB signaling and synaptic disruption; CA2-targeted Hapln1 overexpression or pharmacological MMP9 inhibition rescued structural, synaptic and behavioral abnormalities.

Key Findings

• Repeated 3% sevoflurane exposure during postnatal days 6-8 caused persistent CA2-specific perineuronal-net degradation in adult mice.
• Epigenetic loss of H3K27me3 at the Mmp9 promoter increased MMP9 expression and disrupted BDNF/TrkB signaling, PSD-95 density, dendritic spines and mEPSC frequency.
• CA2-targeted Hapln1 overexpression and MMP9 inhibition restored perineuronal-net integrity, synaptic function and cognitive behaviors.

Clinical Implications

The findings highlight MMP9, perineuronal-net integrity and the hippocampal CA2 extracellular matrix as potential targets for preventing or mitigating developmental anesthetic neurotoxicity. Translation to pediatric anesthesia requires confirmation in additional species, clinically relevant exposure conditions and human developmental tissue or biomarkers.

Limitations

• The study is based on neonatal mice, and species differences may limit direct extrapolation to human infants.
• The exposure paradigm and developmental timing may not fully represent the dose, duration or clinical context of pediatric anesthesia.

Future Directions

Future work should validate the CA2-MMP9-perineuronal-net pathway in other developmental models, determine whether brief or clinically typical exposures produce similar effects, and identify safe interventions that preserve extracellular matrix integrity without disrupting normal plasticity.