Depression is a common mental disorder affecting around 350 million people worldwide. Although selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants, a significant proportion of depressed patients do not achieve remission with SSRIs. In this study, we show that a serotonin type 3 receptor (5HT3R) agonist induces antidepressant effects as well as hippocampal neurogenesis independent of fluoxetine (a commonly used SSRI). Notably, our histological analysis reveals that 5HT3R and insulin-like growth factor 1 (IGF1) are expressed in the same neurons in the subgranular zone of the hippocampal dentate gyrus. Furthermore, our in vivo microdialysis analysis shows that 5HT3R regulates hippocampal extracellular IGF1 levels, and we also show that 5HT3R-dependent hippocampal neurogenesis is mediated by increased IGF1 levels. Altogether, our findings suggest a novel 5HT3R–IGF1 mechanism that is distinct from fluoxetine-induced responses and that provides a new therapeutic target for depression, especially bringing significant benefits for SSRI-resistant depressed patients.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Fact sheets of WHO media centre: mental disorders. World Health Organization (reviewed in April 2016). Available at www.who.int/mediacentre/factsheets/fs396/en.
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40.
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA et al. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4: 1313–1317.
Zhao C, Deng W, Gage FH . Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132: 645–660.
Jacobs BL, van Praag H, Gage FH . Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000; 5: 262–269.
Sahay A, Hen R . Adult hippocampal neurogenesis in depression. Nat Neurosci 2007; 10: 1110–1115.
Samuels BA, Hen R . Neurogenesis and affective disorders. Eur J Neurosci 2011; 33: 1152–1159.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS . Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104–9119.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–809.
Airan RD, Meltzer LA, Loy M, Gong Y, Chen H, Deisseroth K . High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 2007; 317: 819–823.
Samuels BA, Anacker C, Hu A, Levinstein MR, Pickenhagen A, Tsetsenis T et al. 5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response. Nat Neurosci 2015; 18: 1606–1616.
Morales M, Bloom FE . The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon. J Neurosci 1997; 17: 3157–3167.
Staubli U, Xu FB . Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat. J Neurosci 1995; 15: 2445–2452.
Kondo M, Nakamura Y, Ishida Y, Yamada T, Shimada S . The 5-HT3 A receptor is essential for fear extinction. Learn Mem 2014; 21: 1–4.
Cotman CW, Berchtold NC, Christie LA . Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 2007; 30: 464–472.
van Praag H, Kempermann G, Gage FH . Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999; 2: 266–270.
Kondo M, Nakamura Y, Ishida Y, Shimada S . The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects. Mol Psychiatry 2015; 20: 1428–1437.
Zeitz KP, Guy N, Malmberg AB, Dirajlal S, Martin WJ, Sun L et al. The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J Neurosci 2002; 22: 1010–1019.
Chittajallu R, Craig MT, McFarland A, Yuan X, Gerfen S, Tricoire L et al. Dual origins of functionally distinct O-LM interneurons revealed by differential 5-HT3AR expression. Nat Neurosci 2013; 16: 1598–1607.
Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B . The Largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci 2010; 30: 16796–16808.
Vucurovic K, Gallopin T, Ferezou I, Rancillac A, Chameau P, van Hooft JA et al. Serotonin 3A receptor subtype as an early and protracted marker of cortical interneuron subpopulations. Cereb Cortex 2010; 20: 2333–2347.
Koyama Y, Kondo M, Shimada S . Building a 5-HT3A receptor expression map in the mouse brain. Sci Rep 2017; 7: 42884.
Bachy A, Heaulme M, Giudice A, Michaud JC, Lefevre IA, Souilhac J et al. SR 57227 A: a potent and selective agonist at central and peripheral 5-HT3 receptors in vitro and in vivo. Eur J Pharmacol 1993; 237: 299–309.
Koran LM, Cain JW, Dominguez RA, Rush AJ, Thiemann S . Are fluoxetine plasma levels related to outcome in obsessive-compulsive disorder? Am J Psychiatry 1996; 153: 1450–1454.
Dulawa SC, Holick KA, Gundersen B, Hen R . Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology 2004; 29: 1321–1330.
Tanti A, Westphal WP, Girault V, Brizard B, Devers S, Lequisquet AM et al. Region-dependent and stage-specific effects of stress, environmental enrichment, and antidepressant treatment on hippocampal neurogenesis. Hippocampus 2013; 23: 797–811.
Kondo M, Takei Y, Hirokawa N . Motor protein KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment. Neuron 2012; 73: 743–757.
Franklin KBJ, Paxinos G . The Mouse Brain in Stereotaxic Coordinates, 3rd edn. Academic Press: New York, 2007.
Koyama Y, Hattori T, Shimizu S, Taniguchi M, Yamada K, Takamura H et al. DBZ (DISC1-binding zinc finger protein)-deficient mice display abnormalities in basket cells in the somatosensory cortices. J Chem Neuroanat 2013; 53: 1–10.
Takeda S, Sato N, Ikimura K, Nishino H, Rakugi H, Morishita R . Novel microdialysis method to assess neuropeptides and large molecules in free-moving mouse. Neuroscience 2011; 186: 110–119.
Poncelet M, Perio A, Simiand J, Gout G, Soubrie P, Fur GL . Antidepressant-like effects of SR 57227 A, a 5-HT3 receptor agonist, in rodents. J Neural Transm Gen Sect 1995; 102: 83–90.
Jiang W, Zhang Y, Xiao L, Cleemput JV, Ji SP, Bai G et al. Cannabinoids promotes embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest 2005; 115: 3104–3116.
Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 2008; 59: 399–412.
van Praag H, Schinder AF, Christile BR, Toni N, Palmer TD, Gage FH . Functional neurogenesis in the adult hippocampus. Nature 2002; 415: 1030–1034.
Aberg MA, Aberg ND, Palmer TD, Alborn AM, Carlsson-Skwirut C, Bang P et al. IGF-1 has a direct proliferative effect in adult hippocampal progenitor cells. Mol Cell Neurosci 2003; 24: 23–40.
Hoshaw BA, Malberg JE, Lucki I . Central administration of IGF-1 and BDNF leads to long-lasting antidepressant-like effects. Brain Res 2005; 1037: 204–208.
Bondy C, Werner H, Roberts CT, LeRoith D . Cellular pattern of type-1 insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors 1 and 2. Neuroscience 1992; 46: 909–923.
Moser MB, Moser EI . Functional differentiation in the hippocampus. Hippocampus 1998; 8: 608–619.
Fanselow MS, Dong HW . Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 2010; 65: 7–19.
Kheirbek MA, Hen R . Dorsal vs ventral hippocampal neurogenesis: implications for cognition and mood. Neuropsychopharmacology 2011; 36: 373–374.
Tanti A, Belzung C . Neurogenesis along the septo-temporal axis of the hippocampus: are depression and the action of antidepressants region-specific? Neuroscience 2013; 252: 234–252.
Mohammad H, Marchisella F, Ortega-Martinez S, Hollos P, Eerola K, Komulainen E et al. JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behavior from the neurogenic niche. Mol Psychiatry 2016 e-pub ahead of print 15 November 2016; doi:10.1038/mp.2016.203.
Banasr M, Soumier A, Hery M, Mocaer E, Daszuta A . Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol Psychiatry 2006; 59: 1087–1096.
Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, Mann JJ et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 2009; 34: 2376–2389.
Brooker SM, Gobeske KT, Chen J, Peng CY, Kessler JA . Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment. Mol Psychiatry 2016 e-pub ahead of print 4 October 2016; doi:10.1038/mp.2016.160.
Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G et al. Cannabinoids promotes embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest 2005; 115: 3104–3116.
Wang JW, David DJ, Monckton JE, Battaglia F, Hen R . Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 2008; 28: 1374–1384.
Berton O, Nestler EJ . New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 2006; 7: 137–151.
Castren E, Voikar V, Rantamaki T . Role of neurotrophic factors in depression. Curr Opin Pharmacol 2007; 7: 18–21.
Yan YP, Sailor KA, Vemuganti R, Dempsey RJ . Insulin-like growth factor-1 is an endogeneous mediator of focal ischemia-induced neural progenitor proliferation. Eur J Neurosci 2006; 24: 45–54.
Zhang J, Moats-Staats BM, Ye P, D’Ercole AJ . Expression of insulin-like growth factor system genes during the early postnatal neurogenesis in the mouse hippocampus. J Neurosci Res 2007; 85: 1618–1627.
Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR . Intracerebroventricular infusion of insulin-like growth factor-1 ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience 2001; 107: 603–613.
Anderson MF, Aberg MAI, Nilsson M, Eriksson PS . Insulin-like growth factor-1 and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res 2002; 134: 115–122.
Malberg J, Platt B, Rizzo SJS, Ring RH, Lucki I, Schechter LE et al. Increasing the levels of insulin-like growth factor-1 by an IGF binding protein inhibitor produces anxiolytic and antidepressant-like effects. Neuropsychopharmacology 2007; 32: 2360–2368.
Park SE, Dantzer R, Kelley KW, McCusker RH . Central administration of insulin-like growth factor-1 decreases depressive-like behavior and brain cytokine expression in mice. J Neuroinflammation 2011; 8: 12.
Tanaka KF, Samuels BA, Hen R . Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. Philos Trans R Soc Lond B Biol Sci 2012; 367: 2395–2401.
Tecott LH, Maricq AV, Julius D . Nervous system distribution of the serotonin 5-HT3 receptor mRNA. Proc Natl Acad Sci USA 1993; 90: 1430–1434.
Morales M, Battenberg E, de Lecea L, Sanna PP, Bloom FE . Cellular and subcellular immunolocalization of the type 3 serotonin receptor in the rat central nervous system. Mol Brain Res 1996; 36: 251–260.
Morales M, Battenberg E, de Lecea L, Bloom FE . The type 3 serotonin receptor is expressed in a subpopulation of GABAergic neurons in the rat neocortex and hippocampus. Brain Res 1996; 731: 199–202.
Inta D, Alfonso J, von Engelhardt J, Kreuzberg MM, Meyer AH, van Hooft JA et al. Neurogenesis and widespread forebrain migration of distinct GABAergic neurons from the postnatal subventricular zone. Proc Natl Acad Sci USA 2008; 105: 20994–20999.
Martin P, Gozlan H, Puech AJ . 5-HT3 receptor antagonists reverse helpless behavior rats. Eur J Pharmacol 1992; 212: 73–78.
Ramamoorthy R, Radhakrishnan M, Borah M . Antidepressant-like effects of serotonin type-3 antagonist, ondansetron: an investigation in behavior-based rodent models. Behav Pharmacol 2008; 19: 29–40.
Gupta D, Prabhakar V, Radhakrishnan M . 5HT3 receptors: target for new antidepressant drugs. Neurosci Biobehav Rev 2016; 64: 311–325.
Shimizu K, Kurosawa N, Seki K . The role of the AMPA receptor and 5-HT3 receptor on aggressive behavior and depressive-like symptoms in chronic social isolation-reared mice. Physiol Behav 2016; 153: 70–83.
This work was supported by grants from the Japan Society for the Promotion of Science KAKENHI (No. 16K19764), the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Senri Life Science Foundation, the Nakajima Foundation, the Japan Health Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Life Science Foundation of Japan, the Uehara Memorial Foundation and Public Health Research Foundation.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
About this article
Cite this article
Kondo, M., Koyama, Y., Nakamura, Y. et al. A novel 5HT3 receptor–IGF1 mechanism distinct from SSRI-induced antidepressant effects. Mol Psychiatry 23, 833–842 (2018). https://doi.org/10.1038/mp.2017.87
Cochlear protection against noise exposure requires serotonin type 3A receptor via the medial olivocochlear system
The FASEB Journal (2021)
Constitutive Activity of Serotonin Receptor 6 Regulates Human Cerebral Organoids Formation and Depression-like Behaviors
Stem Cell Reports (2021)
Association between the serum insulin‐like growth factor‐1 concentration in the first trimester of pregnancy and postpartum depression
Psychiatry and Clinical Neurosciences (2021)
Scientific Reports (2020)
Bladder urothelium converts bacterial lipopolysaccharide information into neural signaling via an ATP-mediated pathway to enhance the micturition reflex for rapid defense
Scientific Reports (2020)