Advertisement

Takeda G Protein–Coupled Receptor 5 Modulates Depression-like Behaviors via Hippocampal CA3 Pyramidal Neurons Afferent to Dorsolateral Septum

Published:November 24, 2020DOI:https://doi.org/10.1016/j.biopsych.2020.11.018

      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 PyNs→somatostatin–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 PyNs→somatostatin–GABAergic neurons of dorsolateral septum transmission, suggesting that TGR5 could be a novel target for developing antidepressants.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Maruyama T.
        • Miyamoto Y.
        • Nakamura T.
        • Tamai Y.
        • Okada H.
        • Sugiyama E.
        • et al.
        Identification of membrane-type receptor for bile acids (M-BAR).
        Biochem Biophys Res Commun. 2002; 298: 714-719
        • Schaap F.G.
        • Trauner M.
        • Jansen P.L.
        Bile acid receptors as targets for drug development.
        Nat Rev Gastroenterol Hepatol. 2014; 11: 55-67
        • Pols T.W.
        • Nomura M.
        • Harach T.
        • Lo Sasso G.
        • Oosterveer M.H.
        • Thomas C.
        • et al.
        TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading.
        Cell Metab. 2011; 14: 747-757
        • Thomas C.
        • Gioiello A.
        • Noriega L.
        • Strehle A.
        • Oury J.
        • Rizzo G.
        • et al.
        TGR5-mediated bile acid sensing controls glucose homeostasis.
        Cell Metab. 2009; 10: 167-177
        • Pols T.W.
        • Noriega L.G.
        • Nomura M.
        • Auwerx J.
        • Schoonjans K.
        The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation.
        J Hepatol. 2011; 54: 1263-1272
        • Alemi F.
        • Kwon E.
        • Poole D.P.
        • Lieu T.
        • Lyo V.
        • Cattaruzza F.
        • et al.
        The TGR5 receptor mediates bile acid-induced itch and analgesia.
        J Clin Invest. 2013; 123: 1513-1530
        • Keitel V.
        • Görg B.
        • Bidmon H.J.
        • Zemtsova I.
        • Spomer L.
        • Zilles K.
        • Häussinger D.
        The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain.
        Glia. 2010; 58: 1794-1805
        • Maruyama T.
        • Tanaka K.
        • Suzuki J.
        • Miyoshi H.
        • Harada N.
        • Nakamura T.
        • et al.
        Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice.
        J Endocrinol. 2006; 191: 197-205
        • Vassileva G.
        • Golovko A.
        • Markowitz L.
        • Abbondanzo S.J.
        • Zeng M.
        • Yang S.
        • et al.
        Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation.
        Biochem J. 2006; 398: 423-430
        • McMillin M.
        • Frampton G.
        • Tobin R.
        • Dusio G.
        • Smith J.
        • Shin H.
        • et al.
        TGR5 signaling reduces neuroinflammation during hepatic encephalopathy.
        J Neurochem. 2015; 135: 565-576
        • Lewis N.D.
        • Patnaude L.A.
        • Pelletier J.
        • Souza D.J.
        • Lukas S.M.
        • King F.J.
        • et al.
        A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE) in vivo.
        PLoS One. 2014; 9e100883
        • Elia A.E.
        • Lalli S.
        • Monsurrò M.R.
        • Sagnelli A.
        • Taiello A.C.
        • Reggiori B.
        • et al.
        Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.
        Eur J Neurol. 2016; 23: 45-52
        • Liang H.
        • Matei N.
        • McBride D.W.
        • Xu Y.
        • Tang J.
        • Luo B.
        • Zhang J.H.
        Activation of TGR5 protects blood brain barrier via the BRCA1/Sirt1 pathway after middle cerebral artery occlusion in rats [published correction appears in J Biomed Sci 2020; 27:71].
        J Biomed Sci. 2020; 27: 61
        • Zuo G.
        • Zhang T.
        • Huang L.
        • Araujo C.
        • Peng J.
        • Travis Z.
        • et al.
        Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKCε/ALDH2 pathway after subarachnoid hemorrhage in rats.
        Free Radic Biol Med. 2019; 143: 441-453
        • Eggink H.M.
        • Tambyrajah L.L.
        • van den Berg R.
        • Mol I.M.
        • van den Heuvel J.K.
        • Koehorst M.
        • et al.
        Chronic infusion of taurolithocholate into the brain increases fat oxidation in mice.
        J Endocrinol. 2018; 236: 85-97
        • Yanguas-Casás N.
        • Barreda-Manso M.A.
        • Nieto-Sampedro M.
        • Romero-Ramírez L.
        TUDCA: An agonist of the bile acid receptor GPBAR1/TGR5 with anti-inflammatory effects in microglial cells.
        J Cell Physiol. 2017; 232: 2231-2245
        • Reddy I.A.
        • Smith N.K.
        • Erreger K.
        • Ghose D.
        • Saunders C.
        • Foster D.J.
        • et al.
        Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward.
        PLoS Biol. 2018; 16e2006682
        • Wu X.
        • Liu C.
        • Chen L.
        • Du Y.F.
        • Hu M.
        • Reed M.N.
        • et al.
        Protective effects of tauroursodeoxycholic acid on lipopolysaccharide-induced cognitive impairment and neurotoxicity in mice.
        Int Immunopharmacol. 2019; 72: 166-175
        • Wu X.
        • Lv Y.G.
        • Du Y.F.
        • Chen F.
        • Reed M.N.
        • Hu M.
        • et al.
        Neuroprotective effects of INT-777 against Aβ1-42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.
        Brain Behav Immun. 2018; 73: 533-545
        • Wu X.
        • Lv Y.G.
        • Du Y.F.
        • Hu M.
        • Reed M.N.
        • Long Y.
        • et al.
        Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.
        Prog Neuropsychopharmacol Biol Psychiatry. 2019; 88: 360-374
        • Schoenfeld T.J.
        • McCausland H.C.
        • Morris H.D.
        • Padmanaban V.
        • Cameron H.A.
        Stress and loss of adult neurogenesis differentially reduce hippocampal volume.
        Biol Psychiatry. 2017; 82: 914-923
        • Györfi O.
        • Nagy H.
        • Bokor M.
        • Moustafa A.A.
        • Rosenzweig I.
        • Kelemen O.
        • Kéri S.
        Reduced CA2-CA3 hippocampal subfield volume is related to depression and normalized by l-DOPA in newly diagnosed Parkinson’s disease.
        Front Neurol. 2017; 8: 84
        • Dunn J.D.
        • Orr S.E.
        Differential plasma corticosterone responses to hippocampal stimulation.
        Exp Brain Res. 1984; 54: 1-6
        • Eichenbaum H.
        Hippocampus: Cognitive processes and neural representations that underlie declarative memory.
        Neuron. 2004; 44: 109-120
        • Stewart M.G.
        • Davies H.A.
        • Sandi C.
        • Kraev I.V.
        • Rogachevsky V.V.
        • Peddie C.J.
        • et al.
        Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: A three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities.
        Neuroscience. 2005; 131: 43-54
        • Galea L.A.
        • McEwen B.S.
        • Tanapat P.
        • Deak T.
        • Spencer R.L.
        • Dhabhar F.S.
        Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress.
        Neuroscience. 1997; 81: 689-697
        • Woolley C.S.
        • Gould E.
        • McEwen B.S.
        Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons.
        Brain Res. 1990; 531: 225-231
        • Sousa N.
        • Lukoyanov N.V.
        • Madeira M.D.
        • Almeida O.F.
        • Paula-Barbosa M.M.
        Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement [published correction appears in Neuroscience 2000; 101:483].
        Neuroscience. 2000; 97: 253-266
        • Conrad C.D.
        What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus?.
        Behav Cogn Neurosci Rev. 2006; 5: 41-60
        • Christian K.M.
        • Miracle A.D.
        • Wellman C.L.
        • Nakazawa K.
        Chronic stress-induced hippocampal dendritic retraction requires CA3 NMDA receptors.
        Neuroscience. 2011; 174: 26-36
        • McKittrick C.R.
        • Magariños A.M.
        • Blanchard D.C.
        • Blanchard R.J.
        • McEwen B.S.
        • Sakai R.R.
        Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites.
        Synapse. 2000; 36: 85-94
        • Watanabe Y.
        • Gould E.
        • Cameron H.A.
        • Daniels D.C.
        • McEwen B.S.
        Phenytoin prevents stress- and corticosterone-induced atrophy of CA3 pyramidal neurons.
        Hippocampus. 1992; 2: 431-435
        • Watanabe Y.
        • Gould E.
        • McEwen B.S.
        Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons.
        Brain Res. 1992; 588: 341-345
        • Kilkenny C.
        • Browne W.
        • Cuthill I.C.
        • Emerson M.
        • Altman D.G.
        • NC3Rs Reporting Guidelines Working Group
        Animal research: Reporting in vivo experiments: The ARRIVE guidelines.
        J Gene Med. 2010; 12: 561-563
        • McGrath J.C.
        • Lilley E.
        Implementing guidelines on reporting research using animals (ARRIVE etc.): New requirements for publication in BJP.
        Br J Pharmacol. 2015; 172: 3189-3193
        • Krishnan V.
        • Han M.H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Golden S.A.
        • Covington 3rd, H.E.
        • Berton O.
        • Russo S.J.
        A standardized protocol for repeated social defeat stress in mice [published correction appears in Nat Protoc 2015; 10:643].
        Nat Protoc. 2011; 6: 1183-1191
        • Jiang B.
        • Wang W.
        • Wang F.
        • Hu Z.L.
        • Xiao J.L.
        • Yang S.
        • et al.
        The stability of NR2B in the nucleus accumbens controls behavioral and synaptic adaptations to chronic stress.
        Biol Psychiatry. 2013; 74: 145-155
        • Khandelwal N.
        • Dey S.K.
        • Chakravarty S.
        • Kumar A.
        miR-30 family miRNAs mediate the effect of chronic social defeat stress on hippocampal neurogenesis in mouse depression model.
        Front Mol Neurosci. 2019; 12: 188
        • Henriques-Alves A.M.
        • Queiroz C.M.
        Ethological evaluation of the effects of social defeat stress in mice: beyond the social interaction ratio.
        Front Behav Neurosci. 2016; 9: 364
        • Cheng Y.
        • Rodriguiz R.M.
        • Murthy S.R.
        • Senatorov V.
        • Thouennon E.
        • Cawley N.X.
        • et al.
        Neurotrophic factor-α1 prevents stress-induced depression through enhancement of neurogenesis and is activated by rosiglitazone.
        Mol Psychiatry. 2015; 20: 744-754
        • Cryan J.F.
        • Holmes A.
        The ascent of mouse: Advances in modelling human depression and anxiety.
        Nat Rev Drug Discov. 2005; 4: 775-790
        • Cryan J.F.
        • Mombereau C.
        • Vassout A.
        The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice.
        Neurosci Biobehav Rev. 2005; 29: 571-625
        • Cryan J.F.
        • Valentino R.J.
        • Lucki I.
        Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test.
        Neurosci Biobehav Rev. 2005; 29: 547-569
        • McEwen B.S.
        • Nasca C.
        • Gray J.D.
        Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex.
        Neuropsychopharmacology. 2016; 41: 3-23
        • Duman R.S.
        • Sanacora G.
        • Krystal J.H.
        Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments.
        Neuron. 2019; 102: 75-90
        • Dai S.
        • Hall D.D.
        • Hell J.W.
        Supramolecular assemblies and localized regulation of voltage-gated ion channels.
        Physiol Rev. 2009; 89: 411-452
        • Wiegert J.S.
        • Mahn M.
        • Prigge M.
        • Printz Y.
        • Yizhar O.
        Silencing neurons: Tools, applications, and experimental constraints.
        Neuron. 2017; 95: 504-529
        • Sheehan T.P.
        • Chambers R.A.
        • Russell D.S.
        Regulation of affect by the lateral septum: Implications for neuropsychiatry.
        Brain Res Brain Res Rev. 2004; 46: 71-117
        • Sheehan T.P.
        • Neve R.L.
        • Duman R.S.
        • Russell D.S.
        Antidepressant effect of the calcium-activated tyrosine kinase Pyk2 in the lateral septum.
        Biol Psychiatry. 2003; 54: 540-551
        • Besnard A.
        • Gao Y.
        • TaeWoo Kim M.
        • Twarkowski H.
        • Reed A.K.
        • Langberg T.
        • et al.
        Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses.
        Nat Neurosci. 2019; 22: 436-446
        • Krishnan V.
        • Nestler E.J.
        The molecular neurobiology of depression.
        Nature. 2008; 455: 894-902
        • Krishnan V.
        • Nestler E.J.
        Linking molecules to mood: New insight into the biology of depression.
        Am J Psychiatry. 2010; 167: 1305-1320
        • Pellicciari R.
        • Gioiello A.
        • Macchiarulo A.
        • Thomas C.
        • Rosatelli E.
        • Natalini B.
        • et al.
        Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity.
        J Med Chem. 2009; 52: 7958-7961
        • Klindt C.
        • Reich M.
        • Hellwig B.
        • Stindt J.
        • Rahnenführer J.
        • Hengstler J.G.
        • et al.
        The G protein-coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signaling in liver.
        Cells. 2019; 8: 1467
        • Lazarević S.
        • Đanić M.
        • Goločorbin-Kon S.
        • Al-Salami H.
        • Mikov M.
        Semisynthetic bile acids: A new therapeutic option for metabolic syndrome.
        Pharmacol Res. 2019; 146: 104333
        • Mertens K.L.
        • Kalsbeek A.
        • Soeters M.R.
        • Eggink H.M.
        Bile acid signaling pathways from the enterohepatic circulation to the central nervous system.
        Front Neurosci. 2017; 11: 617
        • McMillin M.
        • DeMorrow S.
        Effects of bile acids on neurological function and disease.
        FASEB J. 2016; 30: 3658-3668
        • Wong L.C.
        • Wang L.
        • D’Amour J.A.
        • Yumita T.
        • Chen G.
        • Yamaguchi T.
        • et al.
        Effective modulation of male aggression through lateral septum to medial hypothalamus projection.
        Curr Biol. 2016; 26: 593-604
        • Luo A.H.
        • Tahsili-Fahadan P.
        • Wise R.A.
        • Lupica C.R.
        • Aston-Jones G.
        Linking context with reward: A functional circuit from hippocampal CA3 to ventral tegmental area.
        Science. 2011; 333: 353-357
        • Risold P.Y.
        • Swanson L.W.
        Connections of the rat lateral septal complex.
        Brain Res Brain Res Rev. 1997; 24: 115-195
        • Brisch R.
        • Bernstein H.G.
        • Dobrowolny H.
        • Krell D.
        • Stauch R.
        • Trübner K.
        • et al.
        A morphometric analysis of the septal nuclei in schizophrenia and affective disorders: Reduced neuronal density in the lateral septal nucleus in bipolar disorder.
        Eur Arch Psychiatry Clin Neurosci. 2011; 261: 47-58
        • Muigg P.
        • Hoelzl U.
        • Palfrader K.
        • Neumann I.
        • Wigger A.
        • Landgraf R.
        • Singewald N.
        Altered brain activation pattern associated with drug-induced attenuation of enhanced depression-like behavior in rats bred for high anxiety.
        Biol Psychiatry. 2007; 61: 782-796