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 underfunctioning 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-naïve and CUS-exposed mice, while FXR short hairpin RNA (shRNA) ameliorated such symptoms in CUS-exposed mice. The behavioral effects of FXR were 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.
['Hu|Wenfeng|W|', 'Wu|Jingjing|J|', 'Ye|Ting|T|', 'Chen|Zhuo|Z|', 'Tao|Jinhua|J|', 'Tong|Lijuan|L|', 'Ma|Kai|K|', 'Wen|Jie|J|', 'Wang|Hui|H|', 'Huang|Chao|C|']
D000818:Animals D001522:Behavior, Animal D019208:Brain-Derived Neurotrophic Factor D056547:CA1 Region, Hippocampal D017362:Cyclic AMP Response Element-Binding Protein D003593:Cytoplasm D003863:Depression D004195:Disease Models, Animal D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D021381:Protein Transport D018160:Receptors, Cytoplasmic and Nuclear D014157:Transcription Factors
CRTC2 FXR CREB Depression BDNF