Farnesoid X receptor-mediated cytoplasmic translocation of CRTC2 disrupts CREB-BDNF signaling in hippocampal CA1 and leads to the development of depression-like behaviors in mice.

BACKGROUND We recently identified neuronal expression of farnesoid X receptor (FXR), a bile acid receptor known to impair autophagy by inhibiting cyclic adenosine monophosphate response element-binding protein (CREB), a protein whose under-functioning is linked to neuroplasticity and depression. In this study, we hypothesize that FXR may mediate depression via a CREB-dependent mechanism. METHODS Depression was induced in male C57BL6/J mice via chronic unpredictable stress (CUS). Subjects underwent behavioral testing to identify depression-like behaviors. A variety of molecular biology techniques including viral-mediated gene transfer, Western blot, co-immunoprecipitation, and immunofluorescence were used to correlate depression-like behaviors with underlying molecular and physiological events. RESULTS Overexpression of FXR, whose levels were upregulated by CUS in hippocampal CA1, induced or aggravated depression-like behaviors in stress-naive and CUS-exposed mice, while FXR shRNA ameliorated such symptoms in CUS-exposed mice. The behavioral effects of FXR are found to be associated with changes in CREB-brain-derived neurotrophic factor (BDNF) signaling, as FXR overexpression aggravated CUS-induced reduction in BDNF levels while the use of FXR shRNA or disruption of FXR-CREB signaling reversed the CUS-induced reduction in the phosphorylated CREB and BDNF levels. Molecular analysis revealed that FXR shRNA prevented CUS-induced cytoplasmic translocation of CREB-regulated transcription coactivator 2 (CRTC2); CRTC2 overexpression and CRTC2 shRNA abrogated the regulatory effect of FXR overexpression or FXR shRNA on CUS-induced depression-like behaviors. CONCLUSIONS In stress conditions, increased FXR in the CA1 inhibits CREB by targeting CREB and driving the cytoplasmic translocation of CRTC2. Uncoupling of the FXR-CREB complex may be a novel strategy for depression treatment.