TGR5 dysfunction underlies chronic social defeat stress via cAMP/PKA signaling pathway in the hippocampus

Major depressive disorder (MDD) is a debilitating mental health disorder that has a wide impact on many patients and has imposed a heavy burden on society in recent years. However, the specific pathogenesis of depression remains to be elucidated. Numerous studies have shown that metabolic disorders and molecules play important roles in MDD. Here, we demonstrate a preliminary mechanism through which TGR5 functions in the hippocampus during bile acid synthesis dysfunction in mice subjected to chronic social defeat stress (CSDS). According to the enzyme-linked immunosorbent assay (ELISA), susceptible mice subjected to CSDS presented reduced expression of key bile acid enzymes in the serum and total bile acids (TBAs) in the hippocampus. The expression of the bile acid-related receptor TGR5 in the hippocampus was lower in CSDS-exposed susceptible mice than in control mice. By analyzing the potential downstream signaling pathways of TGR5, we found that specific TGR5/cAMP/PKA regulation effectively increased the plasticity of Schaffer collateral (SC)-CA1 synapses in the hippocampus and further alleviated anxiety- and depression-like behavior in susceptible mice. These findings suggest that CSDS susceptibility is accompanied by dysfunction of TGR5 in the hippocampus and the downstream cAMP/PKA signaling pathway. Activating cAMP/PKA signaling can ameliorate behavioral deficits in susceptible mice. This study may support the development of potential effective pharmacotherapies for the treatment of MDD.