Neonatal sevoflurane exposure disrupts oligodendroglial development and TGF-β-associated signaling in the prefrontal cortex and hypothalamus, with persistent behavioral deficits.

BACKGROUND: Repeated exposure to general anesthetics during early brain development may cause persistent neurobehavioral abnormalities, but the contribution of oligodendroglial dysfunction remains unclear. We examined whether neonatal sevoflurane exposure alters oligodendroglial development, myelin basic protein (MBP), and transforming growth factor-β (TGF-β)-associated signaling in the medial prefrontal cortex (mPFC) and hypothalamus. METHODS: C57BL/6 mouse pups received 3% sevoflurane in 40% O2 for 2 h daily on postnatal days 6-8. Motor and social behaviors were assessed at P30-P32. RNA sequencing, qPCR, immunofluorescence, and Western blotting assessed oligodendroglial markers, MBP, and TGF-β1. Recombinant mouse TGF-β1 was administered intranasally, and RepSox was used to interfere with TGF-β receptor I/ALK5-related signaling. RESULTS: Sevoflurane impaired rotarod and balance-beam performance, social interaction, and social recognition memory without changing habituation distance. Transcriptomic analysis indicated relative suppression of the TGF-β signaling pathway gene set. At P8 and P56, sevoflurane reduced SOX10- and OLIG2-positive cell densities and the proportion of APC+SOX10+ cells among total SOX10+ cells in the mPFC and arcuate nucleus. MBP immunoreactivity and mPFC MBP protein abundance were reduced at P56. Regional TGF-β1 immunoreactivity and mPFC TGF-β1-immunoreactive protein abundance were also reduced. Intranasal TGF-β1 increased detectable TGF-β1 abundance and partially improved behavioral outcomes. CONCLUSION: Neonatal sevoflurane exposure is associated with persistent oligodendroglial and MBP abnormalities. Convergent transcriptomic, protein, and pharmacological findings support altered TGF-β-associated signaling as a contributor to the long-term phenotype.