USP11 drives stress-induced synaptic structural deficits and depression-like behaviors through GSK3β/mTOR signaling.

Major depressive disorder (MDD) is a highly disabling psychiatric condition characterized by profound synaptic dysfunction-particularly in the prefrontal cortex-which constitutes a core neuropathological hallmark of the disease. Nevertheless, the molecular mechanisms linking ubiquitination dynamics to stress-associated synaptic structural deficits remain poorly defined. In this study, we identified USP11, an X-linked deubiquitinating enzyme, as a key upstream regulator of the GSK3β/mTOR signaling cascade and the resultant synaptic structural impairments induced by chronic stress. In mice exposed to chronic unpredictable mild stress (CUMS), USP11 expression in the prefrontal cortex was markedly elevated, accompanied by aberrant phosphorylation of GSK3β and mTOR. Immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation analyses verified a specific interaction between USP11 and GSK3β. Subsequent biochemical and cellular assays demonstrated that USP11 directly deubiquitinates GSK3β, modulates its Ser9 phosphorylation level, and consequently alters its enzymatic activity. Functional investigations using transgenic mice and primary neuronal cultures revealed that USP11 acts as a negative regulator of synaptic integrity. Strikingly, USP11 deficiency conferred robust protection against stress-induced synaptic injury and behavioral impairments by restoring synaptic protein expression, preserving neuronal ultrastructure, and ameliorating depressive-like behaviors. Collectively, these findings delineate a critical USP11-GSK3β/mTOR-synaptic plasticity axis underlying depression-related neuropathology and underscore USP11 as a promising therapeutic target for synaptic preservation and neuroprotection in MDD.