Astrocytic FTO-dependent m6A demethylation drives sevoflurane-induced perioperative neurocognitive disorders in mice.

Summary

Sevoflurane selectively upregulates astrocytic FTO in the medial prefrontal cortex, causally driving perioperative neurocognitive deficits via m6A demethylation of GLT‑1 mRNA and aberrant glutamatergic signaling. Astrocyte-specific FTO deletion rescues synaptic and calcium abnormalities and cognition, while SAMe normalizes m6A and improves behavior, nominating epitranscriptomic modulation as a therapeutic avenue.

Key Findings

• Sevoflurane increased astrocytic, but not neuronal/endothelial, FTO in mouse mPFC.
• Astrocyte-specific FTO knockout mitigated, while overexpression exacerbated, sevoflurane-induced cognitive deficits.
• FTO mediated m6A demethylation of GLT-1 mRNA, elevating GLT-1 and disrupting glutamatergic transmission.
• SAMe supplementation restored m6A levels and improved cognitive performance; astrocytic FTO deletion rescued synaptic, morphological, and calcium activity abnormalities.

Clinical Implications

Identifies astrocytic FTO and m6A regulation of GLT-1 as targets for peri-anesthetic neuroprotection; supports exploring SAMe or FTO-modulating strategies to prevent PND, while emphasizing need for human validation.

Limitations

• Preclinical mouse study; generalizability to humans and across anesthetic regimens remains untested.
• Predominantly male mice and single brain region focus may limit broader applicability.

Future Directions

Validate astrocytic FTO/m6A signatures and GLT‑1 modulation in human perioperative cohorts; test FTO inhibitors or methyl donors in large-animal models and early-phase trials for PND prevention.