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

ABSTRACT

Sevoflurane is one of the most commonly used general anesthetics in pediatric clinical practice worldwide. Although accumulating preclinical evidence indicates that neonatal sevoflurane exposure causes persistent cognitive impairments, the extracellular mechanisms remain unclear. Herein, we focus on perineuronal nets (PNNs), extracellular matrix (ECM) structures that constrain neuronal excitatory plasticity and are highly enriched in the hippocampal CA2, a region critical for social recognition memory. Neonatal mice repeatedly exposed to 3% sevoflurane (2 h/day, P6‐P8) exhibited persistent CA2‐specific PNN degradation in adulthood. Mechanistically, sevoflurane depleted H3K27me3 at the Mmp9 promoter, elevating matrix metalloproteinase 9 (MMP9) expression. This epigenetic dysregulation impaired BDNF/ TrkB signaling, reduced PSD‐95 puncta density and dendritic spine abundance, and suppressed mEPSC frequency, leading to impaired novel object recognition and social discrimination. Spatial transcriptomics validated CA2‐specific ECM pathway dysregulation. Notably, CA2‐targeted Hapln1 overexpression in the CA2 excitatory neurons of Camk2a‐Cre mice effectively restored PNN integrity, rescued synaptic dysfunction, and reversed cognitive deficits. The pharmacological inhibition of MMP9 yielded comparable neuroprotective effects. Collectively, this study identified PNNs as pivotal mediators of anesthetic neurotoxicity, uncovered a previously unrecognized epigenetic‐ECM coupling mechanism driving developmental brain injury, and highlighted PNN preservation as a promising translational strategy for preventing pediatric anesthesia‐associated cognitive impairment.