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β-arrestin 2 is essential for fluoxetine-mediated promotion of hippocampal neurogenesis in a mouse model of depression

Abstract

Over the last decade, the roles of β-arrestins in the treatment of neuropsychological diseases have become increasingly appreciated. Fluoxetine is the first selective serotonin reuptake inhibitor developed and is approved for the clinical treatment of depression. Emerging evidence suggests that fluoxetine can directly combine with the 5-HT receptor, which is a member of the G protein-coupled receptor (GPCR) family, in addition to suppressing the serotonin transporter. In this study, we prepared a chronic mild stress (CMS)-induced depression model with β-arrestin2−/− mice and cultured adult neural stem cells (ANSCs) to investigate the involvement of the 5-HT receptor-β-arrestin axis in the pathogenesis of depression and in the therapeutic effect of fluoxetine. We found that β-arrestin2 deletion abolished the fluoxetine-mediated improvement in depression-like behaviors and monoamine neurotransmitter levels, although β-arrestin2 knockout did not aggravate CMS-induced changes in mouse behaviors and neurotransmitters. Notably, the β-arrestin2−/− mice had a shortened dendritic length and reduced dendritic spine density, as well as decreased neural precursor cells, compared to the WT mice under both basal and CMS conditions. We further found that β-arrestin2 knockout decreased the number of proliferating cells in the hippocampal dentate gyrus and suppressed the proliferative capability of ANSCs in vitro. Moreover, β-arrestin2 knockout aggravated the impairment of cell proliferation induced by corticosterone and further blocked the fluoxetine-mediated promotion of mouse hippocampal neurogenesis. Mechanistically, we found that the 5-HT2BR-β-arrestin2-PI3K/Akt axis is essential to maintain the modulation of hippocampal neurogenesis in depressed mice. Our study may provide a promising target for the development of new antidepressant drugs.

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Fig. 1: The effect of Arrb2 on the general state of mice with CMS.
Fig. 2: The effect of Arrb2 on depression-like behavior in the fluoxetine-treated CMS-induced mice.
Fig. 3: The effect of Arrb2 on neurotransmitters and metabolites in the fluoxetine-treated CMS-induced mice.
Fig. 4: The effect of Arrb2 on neuronal morphology and dendritic spine density in the fluoxetine-treated CMS-induced mice.
Fig. 5: The effect of Arrb2 on hippocampal neurogenesis in the fluoxetine-treated CMS-induced mice.
Fig. 6: The effect of Arrb2 on the self-renewal of neurospheres and the proliferation of adult neural stem cells in the CORT-induced model.
Fig. 7: The effect of Arrb2 on the PI3K/Akt signaling pathway in the CORT-challenged ANSC model.
Fig. 8: The involvement of the 5-HT2BR-β-arrestin2 axis in the fluoxetine-enhanced proliferation of the CORT-injured ANSCs.

References

  1. 1.

    Abe-Higuchi N, Uchida S, Yamagata H, Higuchi F, Hobara T, Hara K, et al. Hippocampal sirtuin 1 signaling mediates depression-like behavior. Biol Psychiatry. 2016;80:815–26.

    CAS  PubMed  Google Scholar 

  2. 2.

    Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370:851–8.

    PubMed  Google Scholar 

  3. 3.

    Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA. 2010;303:1938–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Vancampfort D, Correll CU, Galling B, Probst M, De Hert M, Ward PB, et al. Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis. World Psychiatry. 2016;15:166–74.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Herbert J, Lucassen PJ. Depression as a risk factor for Alzheimer’s disease: genes, steroids, cytokines and neurogenesis - What do we need to know? Front Neuroendocrinol. 2016;41:153–71.

    CAS  PubMed  Google Scholar 

  6. 6.

    Rajkowska G, Stockmeier CA. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets. 2013;14:1225–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Sanacora G, Banasr M. From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry. 2013;73:1172–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Popova D, Castren E, Taira T. Chronic fluoxetine administration enhances synaptic plasticity and increases functional dynamics in hippocampal CA3-CA1 synapses. Neuropharmacology. 2017;126:250–6.

    CAS  PubMed  Google Scholar 

  10. 10.

    Gemmel M, Harmeyer D, Bogi E, Fillet M, Hill LA, Hammond GL, et al. Perinatal fluoxetine increases hippocampal neurogenesis and reverses the lasting effects of pre-gestational stress on serum corticosterone, but not on maternal behavior, in the rat dam. Behav Brain Res. 2018;339:222–31.

    CAS  PubMed  Google Scholar 

  11. 11.

    Khodanovich M, Kisel A, Kudabaeva M, Chernysheva G, Smolyakova V, Krutenkova E, et al. Effects of fluoxetine on hippocampal neurogenesis and neuroprotection in the model of global cerebral ischemia in rats. Int J Mol Sci. 2018;19:162.

    PubMed Central  Google Scholar 

  12. 12.

    Peng L, Gu L, Li B, Hertz L. Fluoxetine and all other SSRIs are 5-HT2B agonists—importance for their therapeutic effects. Curr Neuropharmacol. 2014;12:365–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Diaz SL, Narboux-Neme N, Boutourlinsky K, Doly S, Maroteaux L. Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants. Eur Neuropsychopharmacol. 2016;26:265–79.

    CAS  PubMed  Google Scholar 

  14. 14.

    Lefkowitz RJ. A brief history of G-protein coupled receptors (Nobel Lecture). Angew Chem Int Ed Engl. 2013;52:6366–78.

    CAS  PubMed  Google Scholar 

  15. 15.

    Wang W, Qiao Y, Li Z. New insights into modes of GPCR activation. Trends Pharmacol Sci. 2018;39:367–86.

    CAS  PubMed  Google Scholar 

  16. 16.

    Salazar N, Munoz D, Kallifatidis G, Singh RK, Jorda M, Lokeshwar BL. The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation. Mol Cancer. 2014;13:198.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Bonnans C, Flaceliere M, Grillet F, Dantec C, Desvignes JP, Pannequin J, et al. Essential requirement for beta-arrestin2 in mouse intestinal tumors with elevated Wnt signaling. Proc Natl Acad Sci USA. 2012;109:3047–52.

    CAS  PubMed  Google Scholar 

  18. 18.

    Ravier MA, Leduc M, Richard J, Linck N, Varrault A, Pirot N, et al. beta-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice. Diabetologia. 2014;57:532–41.

    CAS  PubMed  Google Scholar 

  19. 19.

    Willner P. The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiol Stress. 2017;6:78–93.

    PubMed  Google Scholar 

  20. 20.

    Jia M, Li C, Zheng Y, Ding X, Chen M, Ding J, et al. Leonurine exerts antidepressant-like effects in the chronic mild stress-induced depression model in mice by inhibiting neuroinflammation. Int J Neuropsychopharmacol. 2017;20:886–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Du RH, Wu FF, Lu M, Shu XD, Ding JH, Wu G, et al. Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression. Redox Biol. 2016;9:178–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Commons KG, Cholanians AB, Babb JA, Ehlinger DG. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. 2017;8:955–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Lukas M, Toth I, Reber SO, Slattery DA, Veenema AH, Neumann ID. The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. Neuropsychopharmacology. 2011;36:2159–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Brachman RA, McGowan JC, Perusini JN, Lim SC, Pham TH, Faye C, et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry. 2016;79:776–86.

    CAS  PubMed  Google Scholar 

  25. 25.

    Ramaker MJ, Dulawa SC. Identifying fast-onset antidepressants using rodent models. Mol Psychiatry. 2017;22:656–65.

    CAS  PubMed  Google Scholar 

  26. 26.

    Lu M, Yang JZ, Geng F, Ding JH, Hu G. Iptakalim confers an antidepressant effect in a chronic mild stress model of depression through regulating neuro-inflammation and neurogenesis. Int J Neuropsychopharmacol. 2014;17:1501–10.

    CAS  PubMed  Google Scholar 

  27. 27.

    Kong H, Zeng XN, Fan Y, Yuan ST, Ge S, Xie WP, et al. Aquaporin-4 knockout exacerbates corticosterone-induced depression by inhibiting astrocyte function and hippocampal neurogenesis. CNS Neurosci Ther. 2014;20:391–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Fan Z, Lu M, Qiao C, Zhou Y, Ding JH, Hu G. MicroRNA-7 enhances subventricular zone neurogenesis by inhibiting NLRP3/Caspase-1 axis in adult neural stem cells. Mol Neurobiol. 2016;53:7057–69.

    CAS  PubMed  Google Scholar 

  29. 29.

    Chetty S, Friedman AR, Taravosh-Lahn K, Kirby ED, Mirescu C, Guo F, et al. Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus. Mol Psychiatry. 2014;19:1275–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Yaman OM, Erman H, Guner I, Tok OE, Pala M, Esrefoglu M, et al. Remote myocardial injury: the protective role of fluoxetine. Can J Physiol Pharmacol. 2018;96:319–27.

    CAS  PubMed  Google Scholar 

  31. 31.

    Di Rosso ME, Sterle HA, Cremaschi GA, Genaro AM. Beneficial effect of fluoxetine and sertraline on chronic stress-induced tumor growth and cell dissemination in a mouse model of lymphoma: crucial role of antitumor immunity. Front Immunol. 2018;9:1341. https://doi.org/10.3389/fimmu.2018.01341.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Ghosh S, Choudhury S, Mukherjee S, Gupta P, Chowdhury O, Baral R, et al. Fluoxetine triggers selective apoptosis in inflammation-induced proliferating (Ki-67(high)) thymocytes. Immunol Cell Biol. 2019;97:470–84.

    CAS  PubMed  Google Scholar 

  33. 33.

    Hu HM, Li B, Wang XD, Guo YS, Hui H, Zhang HP, et al. Fluoxetine is neuroprotective in early brain injury via its anti-inflammatory and anti-apoptotic effects in a rat experimental subarachnoid hemorrhage model. Neurosci Bull. 2018;34:951–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Casarini L, Reiter E, Simoni M. beta-arrestins regulate gonadotropin receptor-mediated cell proliferation and apoptosis by controlling different FSHR or LHCGR intracellular signaling in the hGL5 cell line. Mol Cell Endocrinol. 2016;437:11–21.

    CAS  PubMed  Google Scholar 

  35. 35.

    Kallifatidis G, Munoz D, Singh RK, Salazar N, Hoy JJ, Lokeshwar BL. Beta-arrestin-2 counters CXCR7-mediated EGFR transactivation and proliferation. Mol Cancer Res. 2016;14:493–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kong Z, Deng T, Zhang M, Zhao Z, Liu Y, Luo L, et al. Beta-arrestin1-mediated inhibition of FOXO3a contributes to prostate cancer cell growth in vitro and in vivo. Cancer Sci. 2018;109:1834–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Lazarov O, Hollands C. Hippocampal neurogenesis: learning to remember. Prog Neurobiol. 2016;138-140:1–18.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Toda T, Gage FH. Review: adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res. 2018;373:693–709.

    PubMed  Google Scholar 

  39. 39.

    Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: from monoamines to the neurogenesis hypothesis model - are we there yet? Behav Brain Res. 2018;341:79–90.

    CAS  PubMed  Google Scholar 

  40. 40.

    Micheli L, Ceccarelli M, D’Andrea G, Tirone F. Depression and adult neurogenesis: positive effects of the antidepressant fluoxetine and of physical exercise. Brain Res Bull. 2018;143:181–93.

    CAS  PubMed  Google Scholar 

  41. 41.

    Tao Y, Ma L, Liao Z, Le Q, Yu J, Liu X, et al. Astroglial beta-arrestin1-mediated nuclear signaling regulates the expansion of neural precursor cells in adult hippocampus. Sci Rep. 2015;5:15506.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Wang Y, Jin L, Song Y, Zhang M, Shan D, Liu Y, et al. Beta-arrestin 2 mediates cardiac ischemia-reperfusion injury via inhibiting GPCR-independent cell survival signalling. Cardiovasc Res. 2017;113:1615–26.

    CAS  PubMed  Google Scholar 

  43. 43.

    Eichel K, Jullie D, von Zastrow M. Beta-arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol. 2016;18:303–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Manago F, Espinoza S, Salahpour A, Sotnikova TD, Caron MG, Premont RT, et al. The role of GRK6 in animal models of Parkinson’s disease and L-DOPA treatment. Sci Rep. 2012;2:301.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Prof. Gang Pei in Tongji University for providing β-arrestin2 knockout mice. The work reported herein was supported by the grants from the National Natural Science Foundation of China (No. 81922066, No. 81773706, No. 81991523, and No. 81630099) and the Drug Innovation Major Project (No. 2018ZX09711001-003-007).

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ML and GH developed the concept of this study; ML and GH designed this study. CXL, YZ, HZ, CWL, ZH, CW, JHD acquired and analyzed data. CXL, YZ, and HZ drafted the figures. ML and CXL drafted the paper.

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Correspondence to Gang Hu or Ming Lu.

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The authors declare no competing interests.

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Li, Cx., Zheng, Y., Zhu, H. et al. β-arrestin 2 is essential for fluoxetine-mediated promotion of hippocampal neurogenesis in a mouse model of depression. Acta Pharmacol Sin 42, 679–690 (2021). https://doi.org/10.1038/s41401-020-00576-2

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Keywords

  • β-arrestin2
  • 5-HT2BR
  • fluoxetine
  • neural stem cell
  • neurogenesis
  • depression

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