m6A/YTHDF1 modulates CAP1-mediated actin turnover and synaptic function to regulate anxiodepressive-like behaviors

Neuroplasticity and synaptic dysfunction are central to depression, yet the underlying mechanisms remain poorly understood. While m6A and its reader YTHDF1 regulate mRNA translation, neuroplasticity and learning behaviors, their role in affective disorders such as depression remains unexplored. This study identifies YTHDF1 as a key regulator of depression pathogenesis. Genetic deletion of YTHDF1 in mice caused anterior cingulate cortex (ACC) hyperactivity, heightened social stress sensitivity, and anxiodepressive-like behaviors after acute social stress. Using multi-omic approaches, we uncovered a critical role for actin cytoskeleton dynamics and identified cyclase-associated protein 1 (CAP1) as a downstream effector of YTHDF1. Loss of YTHDF1 reduced CAP1 expression from early postnatal stages, resulting in F-actin accumulation, impaired synaptic function, and behavioral deficits. Strikingly, early postnatal YTHDF1 re-expression in the ACC restored CAP1 levels, synaptic integrity, and reversed depressive-like phenotypes. These findings establish the m6A/YTHDF1/CAP1 axis as a critical pathway regulating synaptic function and depression. We performed high-throughput RNA sequencing of anterior cingulate cortex (ACC) of adult Ythdf1 wild-type (WT) and knockout (KO) mice. Three replicates were conducted for each genotype. The RNA libraries were sequenced on the illumina NovaseqTM 6000 platform by LC Bio Technology CO.,Ltd (Hangzhou, China).