- YTHDF1 is a critical regulator whose deletion induces ACC hyperactivity, hyperalgesia and anxiodepressive-like behaviours following acute social stress.
- YTHDF1 deficiency reduces CAP1 expression, provoking F-actin accumulation and synaptic dysfunction via dysregulated actin cytoskeleton dynamics.
- Early postnatal ACC re-expression of YTHDF1 or CAP1 restores CAP1, rescues synaptic integrity and reverses anxiodepressive-like behaviours.
Mol Psychiatry. 2026 Sep 4. doi: 10.1038/s41380-026-03840-9. Online ahead of print.
ABSTRACT
Neuroplasticity and synaptic dysfunction are central to the pathophysiology of depression, yet their underlying mechanisms remain not fully understood. Here, we identify the m6A reader protein YTHDF1 as a key regulator of depression pathogenesis. Mice with genetic deletion of Ythdf1 exhibited anterior cingulate cortex (ACC) hyperactivity, hyperalgesia, heightened social stress sensitivity, and anxiodepressive-like behaviors following acute social stress. Using multi-omics approaches, we linked these effects to dysregulated actin cytoskeleton dynamics and identified cyclase-associated protein 1 (CAP1) as a downstream effector of YTHDF1. YTHDF1 deficiency reduced CAP1 expression from early postnatal stages, leading to F-actin accumulation, impaired synaptic function, and behavioral deficits. Strikingly, early postnatal re-expression of YTHDF1 in the ACC normalized CAP1 levels, restored synaptic integrity, and reversed depressive-like phenotypes. Similarly, CAP1 re-expression was sufficient to alleviate stress-induced psychomotor retardation and anxiety. Our findings establish the YTHDF1-CAP1 axis as a critical pathway governing synaptic function and depressive behaviors.
PMID:42697900 | DOI:10.1038/s41380-026-03840-9
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