Epigenetic Dysregulation of the Wnt/β-Catenin Pathway via FTO-m6A in the mPFC Contributes to Autism-Like Behaviors.

Post-transcriptional modifications of RNA, particularly m6A methylation, are emerging as critical epigenetic regulators of neurodevelopment and behavior. Although the RNA demethylase, fat mass and obesity-associated (FTO) protein has been implicated in autism spectrum disorder (ASD), the precise mRNA targets and downstream molecular pathways through which it governs behavior remain unclear. Here, we identify a significant upregulation of FTO in the medial prefrontal cortex (mPFC) of BTBR mice, a well-established ASD model. Targeted knockdown of Fto in the mPFC successfully ameliorates core ASD-like behavioral deficits. Mechanistically, m6A methylome analysis reveals Ctnnb1 (encoding β-catenin) as a direct functional substrate of FTO. FTO-mediated m6A demethylation of Ctnnb1 mRNA enhances its expression, driving aberrant hyperactivation of the Wnt/β-catenin signaling pathway. Translating these molecular insights, systemic pharmacological inhibition of the Wnt/β-catenin pathway partially rescues the behavioral phenotypes in BTBR mice. Importantly, in vivo fiber photometry revealed that this pharmacological rescue is accompanied by the restoration of impaired calcium dynamics in mPFC excitatory neurons during novel object recognition. Together, these findings elucidate a novel epitranscriptomic mechanism whereby the mPFC FTO-m6A-Ctnnb1 axis drives ASD-like phenotypes. Furthermore, they provide preclinical evidence that targeting this specific epigenetic and signaling pathway represents a highly viable pharmacological strategy for ASD intervention.