Neonatal sevoflurane anesthesia induces persistent cognitive deficits in mice through CypD-dependent mitochondrial...

Repeated neonatal sevoflurane anesthesia induces cognitive impairment in adulthood, but its neuropathological mechanisms remain unclear. Parvalbumin (PV) interneurons, which rely heavily on mitochondrial stability, are susceptible to anesthesia. Mitochondrial matrix protein Cyclophilin D (CypD) is involved in cognition by regulating the mitochondrial function. To investigate the role of CypD in PV interneurons in neonatal sevoflurane-induced cognitive impairment, postnatal day 6-8 mice were exposed to 3 % sevoflurane 2 h daily in 30 % oxygen/70 % air. Behavioral tests revealed that repeated sevoflurane exposure induced persistent deficits in novel object recognition, social interaction, and Morris water maze performance; however, these cognitive impairments were prevented in mice with conditional CypD knockout in PV interneurons (Ppif^F/F-PV^Cre). Immunofluorescence and Western blot analysis of hippocampal tissues demonstrated upregulated CypD expression in PV interneurons following anesthesia, accompanied by downregulation of vesicular GABA transporter (VGAT); however, these effects were absent in Ppif^F/F-PV^Cre mice. Furthermore, sevoflurane reduced mitochondrial membrane potential (MMP) and enhanced oxidative stress. Calcium imaging showed that sevoflurane disrupted mitochondrial calcium homeostasis. Nevertheless, CypD ablation preserved MMP, attenuated oxidative stress, and maintained calcium homeostasis. Synaptic plasticity evaluation using Golgi staining and whole-cell patch-clamp recordings confirmed that sevoflurane reduced dendritic spine density and decreased frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs), which was rescued by PV-interneuron-specific CypD deletion. These findings indicate that neonatal exposure to sevoflurane impairs cognition through CypD-dependent mitochondrial dysfunction in PV interneurons, and that targeting CypD in these neurons represents a viable neuroprotective strategy.