FTO-mediated m6A depletion drives prenatal prednisone exposure-induced cortical neurogenesis deficits and long-term anxiety-depression-like behaviors in offspring

Prednisone is widely used to treat pregnancy-complicated autoimmune diseases, but the impact of prenatal prednisone exposure (PPE) on offspring neurodevelopment is unclear. Clinical follow-up using the Ages and Stages Questionnaires (ASQ:SE-2 and ASQ-3) revealed a strong association between PPE and neurodevelopmental abnormalities. In a rat model, PPE significantly inhibited the proliferation and differentiation of cortical radial glial cells (RGCs), impairing cortical neurogenesis and leading to anxiety- and depression-like behaviors. Mechanistically, PPE upregulated fat mass and obesity-associated protein (FTO) nuclear recruitment in RGCs, depleting N 6-methyladenosine (m6A) modifications and stabilizing Crebbp/Ep300 mRNA, which activated genes related to cell cycle arrest and neuronal differentiation via histone 3 at lysine 27 acetylation (H3K27ac) modifications. The key role of FTO in PPE-induced neurodevelopmental impairments was confirmed using Ep300 shRNA, Fto overexpression lentivirus, and a conditional Fto knockout mouse model (Fto fl/fl ; Nestin-Cre). Notably, early postnatal neuregulin-1 supplementation promoted RGCs proliferation and alleviated behavioral abnormalities.