Inhibition of FKBP51 alleviates depressive-like behaviors via AKT/mTOR-dependent autophagy and synaptic plasticity

BACKGROUND: Depression is a major global health problem, the pathogenesis of which remains to be elucidated, and current antidepressants exhibit limited efficacy. FK506-binding protein 51 (FKBP51) has been identified as a key modulator of stress-related psychiatric disorders, yet further research is required in depression. METHODS: We investigated the role of hippocampal FKBP51 using a chronic unpredictable mild stress rat model and stereotaxic FKBP5 overexpression. The antidepressant effect of the FKBP51 inhibitor, selective antagonist of FKBP51 by induced fit 2 (SAFit2), was evaluated in corticosterone-induced depression model both in vivo and in vitro. Molecular and structural changes were analyzed using quantitative polymerase chain reaction, Western blotting, Golgi-Cox staining, transmission electron microscopy, and immunofluorescence. SH-SY5Y cells were utilized to examine autophagic flux and dissect downstream pathways. RESULTS: Hippocampal FKBP51 was upregulated in chronic unpredictable mild stress-susceptible rats and correlated with depressive-like behaviors. Functionally, FKBP5 overexpression mimicked stress pathologies, inducing autophagic hyperactivation and suppressing AKT/mTOR signaling. Mechanistically, corticosterone enhanced the recruitment of the phosphatase PHLPP to FKBP51, thereby inhibiting the AKT/mTOR pathway. SAFit2 treatment disrupted the FKBP51-PHLPP interaction, reactivated the AKT/mTOR pathway, normalized autophagic flux, restored neuroplasticity, and attenuated depressive-like behaviors. CONCLUSIONS: Stress-induced FKBP51 upregulation drives depressive-like behaviors in male rats by impairing neuroplasticity and inducing autophagic hyperactivation via the PHLPP-AKT-mTOR pathway. SAFit2 exhibited antidepressant-like effects by targeting this axis, highlighting FKBP51 as a potential target for depression.