FKBP5 deficiency selectively impairs NMDAR-dependent long-term depression via enhanced calcineurin activity:...

The co-chaperone FK506 binding protein 51 (FKBP5) is known to negatively regulate glucocorticoid receptors (GRs), and its genetic polymorphisms have been implicated in stress resilience in clinical studies. FKBP5-deficient animals are known to exhibit stress resilience, but minimal alterations in synaptic transmission were observed in the hippocampus. Given the crucial role of the hippocampus in GR regulation, we investigated the function of FKBP5 in the bidirectional synaptic plasticity in the hippocampus of male mice and found intact long-term potentiation (LTP) induction even in the absence of FKBP5. Furthermore, GR activation by corticosterone incubation blocked the LTP induction in controls but not in FKBP5 knockout (KO) mice. Interestingly, low-frequency stimulation (LFS) -induced long-term depression (LTD) was selectively impaired in male KO mice. Importantly, impaired LTD in KO mice was mediated by increased calcineurin expression, highlighting the importance of FKBP5 in regulating synaptic plasticity through its interaction with GR and calcineurin. Further research on the FKBP5-related signaling pathways may provide insights into the molecular mechanisms underlying stress resilience and potential therapeutic targets for psychiatric disorders associated with stress dysregulation.