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Takeda G-Protein-Coupled Receptor 5 Modulates Depression-Like
AAV-GCaMP6s was used to monitor CA3 PyNs activity on a real-time fiber photometry. hM4Di-mCherry was used for chemogenetic inhibition to determine the antidepressant-like effects of TGR5. AAV- iGluSnFR was used to track endogenous glutamate dynamics in DLS. (All viruses were packaged by BrainVTA)
The viruses used in this article from BrainVTA are in the table below
Calcium sensors  PT-0110 AAV-CaMKIIα-GCaMP6s
Chemogenetics  PT-0017 AAV-CaMKIIα-hM4Di-mCherry
Neurotransmitter sensors  PT-1140 AAV-hSyn-iGluSnFR(A184s)
Hao Wang, Yuan-Zhi Tan, Rong-Hao Mu, Su-Su Tang, Xiao Liu, Shu-Yun Xing, Yan Long, Dan-Hua Yuan, Hao Hong
Pub Date: 2020-11-25,  DOI: https://doi.org/10.1016/j.biopsych.2020.11.018,  Email: [email protected]
Background: Takeda G-protein-coupled receptor 5 (TGR5) is recognized as a promising target for type 2 diabetes and metabolic syndrome; its expression has been demonstrated in brain and is thought to be neuroprotective. Here, we hypothesize that dysfunction of central TGR5 may contribute to the pathogenesis of depression.
Methods: In well-established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression, using fiber photometry, optogenetic, chemogenetic, pharmacological, molecular profiling techniques and behavioral tests, we investigated the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of neuronal circuit in depression (for in vivo studies, n = 10; for in vitro studies, n = 5-10).
Results: Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs. Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777, a specific agonist, protected against CSDS and CRS, exerting significant antidepressant-like effects that were mediated via CA3 PyNs activation. Conversely, genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behaviors. Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in TGR5 knockout mice exposed to CSDS or CRS. Silencing and stimulation of CA3 PyNs→somatostatin (SST)-GABAergic neurons of dorsolateral septum (DLS) circuit bidirectionally regulated depression-like behaviors, and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.
Conclusions: These findings indicate that TGR5 can regulate depression via CA3 PyNs→SST-GABAergic neurons of DLS transmission, suggesting that TGR5 could be a novel target for developing antidepressants.
Fig1. TGR5 enhances neurotransmission of CA3→dorsolateral septum (DLS) circuit that regulates depression-like behaviors
To investigate the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of neuronal circuit in depression, the authors used fiber photometry, optogenetic, chemogenetic, pharmacological, molecular profiling techniques and behavioral tests to study. The results showed TGR5 in CA3 PyNs is involved in the pathogenesis of depression through CA3 PyNs→SST-GABAergic neurons of DLS circuit, and it is a new molecular target for therapeutically protecting against depression.

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