FKBP51 REGULATES BDNF/TRKB SIGNALING AND STRESS-DRIVEN SYNAPTIC PLASTICITY

Psychosocial stress profoundly influences brain structure and function, largely through glucocorticoids acting via the glucocorticoid receptor (GR). Stress and GR signaling leads to rapid and long-lasting plasticity alterations, yet the underlying molecular mechanisms remain incompletely understood. The stress-responsive co-chaperone FK506-binding protein 51 (FKBP51) represents a promising candidate mediator of these processes. FKBP51 is strongly induced by glucocorticoids and functions as a molecular scaffold regulating protein–protein interactions and posttranslational modifications. Although FKBP51 has been implicated in neuronal morphology and neurite outgrowth, its role in stress-driven neuroplasticity remains unclear. We identified FKBP51 as a critical modulator of tyrosine kinase receptor B (TrkB) signaling, a central regulator of synaptic plasticity. Using human neuroblastoma cells, we demonstrated that glucocorticoids promote FKBP51-dependent translocation of TrkB to the plasma membrane by recruiting cyclin-dependent kinase 5 (CDK5). This effect requires SUMOylated FKBP51 and results in increased TrkB stability. Mechanistically, FKBP51 reduces TrkB ubiquitination by modulating interactions with the ubiquitin ligase TRAF6 and the scaffolding protein p62, thereby protecting TrkB from proteasomal degradation. In Fkbp5^-/- hippocampal slices, BDNF-induced synaptic potentiation is reduced, accompanied by impaired TrkB membrane localisation and CDK5-mediated phosphorylation. Consistent with molecular findings, FKBP5-deficient mice displayed attenuated behavioral responses to intranasal BDNF in the forced swim test, indicating compromised stress-coping capacity. Together, our results reveal FKBP51 as a key integrator of glucocorticoid and BDNF/TrkB signaling pathways, mediating stress-induced synaptic plasticity and adaptive behavioral responses. These findings provide new insights into the molecular interface between stress and neuroplasticity with potential relevance for stress-related psychiatric disorders.