Takeda G Protein-Coupled Receptor 5 Modulates Depression-like Behaviors via Hippocampal CA3 Pyramidal Neurons Afferent to Dorsolateral Septum.
Biol Psychiatry
; 89(11): 1084-1095, 2021 06 01.
Article
en En
| MEDLINE
| ID: mdl-33536132
ABSTRACT
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 the 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, we investigated the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of the neuronal circuit in depression (for in vivo studies, n = 10; for in vitro studies, n = 5-10) using fiber photometry; optogenetic, chemogenetic, pharmacological, and molecular profiling techniques; and behavioral tests.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 PyN 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 PyNsâsomatostatin-GABAergic (gamma-aminobutyric acidergic) neurons of the dorsolateral septum 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 PyNsâsomatostatin-GABAergic neurons of dorsolateral septum transmission, suggesting that TGR5 could be a novel target for developing antidepressants.Palabras clave
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Células Piramidales
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Receptores Acoplados a Proteínas G
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Depresión
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Biol Psychiatry
Año:
2021
Tipo del documento:
Article
País de afiliación:
China