Antidepressant Drugs Correct the Imbalance Between proBDNF/p75NTR/Sortilin and Mature BDNF/TrkB in the Brain of Mice with Chronic Stress

  • C. R. Yang
  • X. Y. Zhang
  • Y. Liu
  • J. Y. Du
  • R. Liang
  • M. Yu
  • F. Q. Zhang
  • X. F. Mu
  • F. Li
  • L. Zhou
  • F. H. Zhou
  • F. J. Meng
  • S. Wang
  • D. MingEmail author
  • X. F. ZhouEmail author
Original Article


Depression is a worldwide problem with a great social and economic burden in many countries. In our previous research, we found that the expression of proBDNF/p75NTR/sortilin is upregulated in patients with major depressive disorder. In addition, the treatment of proBDNF antibodies reversed both the depressive behaviors and the reduced BDNF mRNA detected in our rodent chronic stress models. Antidepressant drugs are usually only effective in a subpopulation of patients with major depression with a delayed time window of 2–4 weeks to exert their efficacy. The mechanism underlying such delayed response is not known. In this study, we hypothesize that antidepressant drugs exert their therapeutic effect by modulating proBDNF/p75NTR and mature BDNF/TrkB signaling pathways. To test the hypothesis, C57 mice were randomly divided into normal control, chronic unpredictable mild stress (CUMS), vehicle (VEH), fluoxetine (FLU), and clozapine (CLO) groups. Behavioral tests (sucrose preference, open field, and tail suspension tests) were performed before and after 4 weeks of CUMS. The gene and protein expression of proBDNF, the neurotrophin receptor (p75NTR), sortilin, and TrkB in the cortex and hippocampus were examined. At the protein level, CUMS induced a significant increase in proBDNF, p75NTR, and sortilin production while the TrkB protein level was found to be lower in the cortex and hippocampus compared with the control group. Consistently, at the mRNA level, p75NTR expression increased with reduced BDNF/TrkB mRNA in both cortex and hippocampus, while sortilin increased only in the hippocampus after CUMS. FLU and CLO treatments of CUMS mice reversed all protein and mRNA expression of the biomarkers in both cortex and hippocampus, except for sortilin mRNA in the cortex and proBDNF in the hippocampus, respectively. This study further confirms that the imbalance between proBDNF/p75NTR/sortilin and mBDNF/TrkB production is important in the pathogenesis of depression. It is likely that antidepressant FLU and antipsychotic CLO exert their antidepressant-like effect correcting the imbalance between proBDNF/p75NTR/sortilin and mBDNF/TrkB.


Depression BDNF proBDNF Fluoxetine Clozapine 


Funding Information

This research was financially supported by grant from The Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2018KJ086).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Ashcroft GW, Sharman DF (1960) 5-Hydroxyindoles in human cerebrospinal fluids. Nature 186:1050–1051CrossRefGoogle Scholar
  2. Bai YY, Ruan CS, Yang CR, Li JY, Kang ZL, Zhou L, Liu D, Zeng YQ, Wang TH, Tian CF, Liao H, Bobrovskaya L, Zhou XF (2016) ProBDNF signaling regulates depression-like behaviors in rodents under chronic stress. Neuropsychopharmacology 41(12):2882–2892CrossRefGoogle Scholar
  3. Bert F, Giacomelli S, Ceresetti D, Zotti CM (2017) World Health Organization framework: multimodal hand hygiene strategy in Piedmont (Italy) health care facilities. J Patient SafGoogle Scholar
  4. Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L, Wong DT, Perry KW (2002) Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology 160(4):353–361CrossRefGoogle Scholar
  5. Castren E, Rantamaki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70(5):289–297CrossRefGoogle Scholar
  6. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62(4):479–493CrossRefGoogle Scholar
  7. Fan YJ, Wu LL, Li HY, Wang YJ, Zhou XF (2008) Differential effects of pro-BDNF on sensory neurons after sciatic nerve transection in neonatal rats. Eur J Neurosci 27(9):2380–2390CrossRefGoogle Scholar
  8. Furuse K, Ukai W, Hashimoto E, Hashiguchi H, Kigawa Y, Ishii T, Tayama M, Deriha K, Shiraishi M, Kawanishi C (2019) Antidepressant activities of escitalopram and blonanserin on prenatal and adolescent combined stress-induced depression model: possible role of neurotrophic mechanism change in serum and nucleus accumbens. J Affect Disord 247:97–104CrossRefGoogle Scholar
  9. Galistu A, Modde C, Pireddu MC, Franconi F, Serra G, D'Aquila PS (2011) Clozapine increases reward evaluation but not overall ingestive behaviour in rats licking for sucrose. Psychopharmacology 216(3):411–420CrossRefGoogle Scholar
  10. Gundersen BB, Briand LA, Onksen JL, Lelay J, Kaestner KH, Blendy JA (2013) Increased hippocampal neurogenesis and accelerated response to antidepressants in mice with specific deletion of CREB in the hippocampus: role of cAMP response-element modulator tau. J Neurosci 33(34):13673–13685CrossRefGoogle Scholar
  11. Jin HJ, Pei L, Li YN, Zheng H, Yang S, Wan Y, Mao L, Xia YP, He QW, Li M, Yue ZY, Hu B (2017) Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression. Sci Rep 7(1):14926CrossRefGoogle Scholar
  12. Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar S (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 14(3):347–353CrossRefGoogle Scholar
  13. Kurita M, Nishino S, Kato M, Numata Y, Sato T (2012) Plasma brain-derived neurotrophic factor levels predict the clinical outcome of depression treatment in a naturalistic study. PLoS One 7(6):e39212CrossRefGoogle Scholar
  14. Lang UE, Hellweg R, Gallinat J (2004) BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychopharmacology 29(4):795–798CrossRefGoogle Scholar
  15. Lee CH, Park JH, Yoo KY, Choi JH, Hwang IK, Ryu PD, Kim DH, Kwon YG, Kim YM, Won MH (2011) Pre- and post-treatments with escitalopram protect against experimental ischemic neuronal damage via regulation of BDNF expression and oxidative stress. Exp Neurol 229(2):450–459CrossRefGoogle Scholar
  16. Li JY, Liu J, Manaph NPA, Bobrovskaya L, Zhou XF (2017) ProBDNF inhibits proliferation, migration and differentiation of mouse neural stem cells. Brain Res 1668:46–55CrossRefGoogle Scholar
  17. Luo L, Li C, Du X, Shi Q, Huang Q, Xu X, Wang Q (2019) Effect of aerobic exercise on BDNF/proBDNF expression in the ischemic hippocampus and depression recovery of rats after stroke. Behav Brain Res 362:323–331CrossRefGoogle Scholar
  18. Malhotra AK, Adler CM, Kennison SD, Elman I, Pickar D, Breier A (1997) Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine. Biol Psychiatry 42(8):664–668CrossRefGoogle Scholar
  19. Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Kenis G, Prickaerts J, Voshaar RC, Elzinga BM (2011) Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry 16(11):1088–1095CrossRefGoogle Scholar
  20. Oved K, Farberov L, Gilam A, Israel I, Haguel D, Gurwitz D, Shomron N (2017) MicroRNA-mediated regulation of ITGB3 and CHL1 is implicated in SSRI action. Front Mol Neurosci 10:355CrossRefGoogle Scholar
  21. Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ (1998) Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 37(12):1553–1561CrossRefGoogle Scholar
  22. Peng S, Li W, Lv L, Zhang Z, Zhan X (2018) BDNF as a biomarker in diagnosis and evaluation of treatment for schizophrenia and depression. Discov Med 26(143):127–136Google Scholar
  23. Rame M, Caudal D, Schenker E, Svenningsson P, Spedding M, Jay TM, Godsil BP (2017) Clozapine counteracts a ketamine-induced depression of hippocampal-prefrontal neuroplasticity and alters signaling pathway phosphorylation. PLoS One 12(5):e0177036CrossRefGoogle Scholar
  24. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301(5634):805–809CrossRefGoogle Scholar
  25. Segi-Nishida E (2017) The effect of serotonin-targeting antidepressants on neurogenesis and neuronal maturation of the hippocampus mediated via 5-HT1A and 5-HT4 receptors. Front Cell Neurosci 11:142CrossRefGoogle Scholar
  26. Serra MP, Poddighe L, Boi M, Sanna F, Piludu MA, Corda MG, Giorgi O, Quartu M (2018) Effect of acute stress on the expression of BDNF, trkB, and PSA-NCAM in the hippocampus of the Roman rats: a genetic model of vulnerability/resistance to stress-induced depression. Int J Mol Sci 19(12)Google Scholar
  27. Shen LL, Manucat-Tan NB, Gao SH, Li WW, Zeng F, Zhu C, Wang J, Bu XL, Liu YH, Gao CY, Xu ZQ, Bobrovskaya L, Lei P, Yu JT, Song W, Zhou HD, Yao XQ, Zhou XF, Wang YJ (2018) The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau. Mol Psychiatry 23(8):1813–1824CrossRefGoogle Scholar
  28. Souery D, Oswald P, Massat I, Bailer U, Bollen J, Demyttenaere K, Kasper S, Lecrubier Y, Montgomery S, Serretti A, Zohar J, Mendlewicz J (2007) Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry 68(7):1062–1070CrossRefGoogle Scholar
  29. Sun Y, Lim Y, Li F, Liu S, Lu JJ, Haberberger R, Zhong JH, Zhou XF (2012) ProBDNF collapses neurite outgrowth of primary neurons by activating RhoA. PLoS One 7(4):e35883CrossRefGoogle Scholar
  30. Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25(22):5455–5463CrossRefGoogle Scholar
  31. Thaler KJ, Morgan LC, Van Noord M, Gaynes BN, Hansen RA, Lux LJ, Krebs EE, Lohr KN, Gartlehner G (2012) Comparative effectiveness of second-generation antidepressants for accompanying anxiety, insomnia, and pain in depressed patients: a systematic review. Depress Anxiety 29(6):495–505CrossRefGoogle Scholar
  32. Xu ZQ, Sun Y, Li HY, Lim Y, Zhong JH, Zhou XF (2011) Endogenous proBDNF is a negative regulator of migration of cerebellar granule cells in neonatal mice. Eur J Neurosci 33(8):1376–1384CrossRefGoogle Scholar
  33. Yang CR, Bai YY, Ruan CS, Zhou HF, Liu D, Wang XF, Shen LJ, Zheng HY, Zhou XF (2015) Enhanced aggressive behaviour in a mouse model of depression. Neurotox Res 27(2):129–142CrossRefGoogle Scholar
  34. Yang CR, Bai YY, Ruan CS, Zhou FH, Li F, Li CQ, Zhou XF (2017) Injection of anti-proBDNF in anterior cingulate cortex (ACC) reverses chronic stress-induced adverse mood behaviors in mice. Neurotox Res 31(2):298–308CrossRefGoogle Scholar
  35. Yang SJ, Song ZJ, Wang XC, Zhang ZR, Wu SB, Zhu GQ (2019) Curculigoside facilitates fear extinction and prevents depression-like behaviors in a mouse learned helplessness model through increasing hippocampal BDNF. Acta Pharmacol SinGoogle Scholar
  36. Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T, Shiina A, Hashimoto T, Kanahara N, Hasegawa T, Enohara M, Kimura A, Iyo M, Hashimoto K (2012) Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One 7(8):e42676CrossRefGoogle Scholar
  37. Zhang Z, Rickard JF, Asgari K, Body S, Bradshaw CM, Szabadi E (2005) Quantitative analysis of the effects of some “atypical” and “conventional” antipsychotics on progressive ratio schedule performance. Psychopharmacology 179(2):489–497CrossRefGoogle Scholar
  38. Zhang F, Luo J, Zhu X (2018) Ketamine ameliorates depressive-like behaviors by tPA-mediated conversion of proBDNF to mBDNF in the hippocampus of stressed rats. Psychiatry Res 269:646–651CrossRefGoogle Scholar
  39. Zhou L, Xiong J, Lim Y, Ruan Y, Huang C, Zhu Y, Zhong JH, Xiao Z, Zhou XF (2013) Upregulation of blood proBDNF and its receptors in major depression. J Affect Disord 150(3):776–784CrossRefGoogle Scholar
  40. Zhou L, Xiong J, Ruan CS, Ruan Y, Liu D, Bao JJ, Zhou XF (2018) ProBDNF/p75NTR/sortilin pathway is activated in peripheral blood of patients with alcohol dependence. Transl Psychiatry 7(11):2CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PathologyThe Second Hospital of Tianjin Medical UniversityTianjinPeople’s Republic of China
  2. 2.School of Pharmacology and Medical ScienceUniversity of South AustraliaAdelaideAustralia
  3. 3.Academy of Medical Engineering and Translational MedicineTianjin UniversityTianjinPeople’s Republic of China
  4. 4.Tianjin Mental Health CenterTianjinPeople’s Republic of China
  5. 5.Department of NeurologySecond Hospital of Tianjin Medical UniversityTianjinPeople’s Republic of China
  6. 6.Department of Clinical LaboratoryQingdao Central HospitalQingdaoPeople’s Republic of China
  7. 7.Department of Anatomy and Neurobiology, School of Basic Medical ScienceCentral South UniversityChangshaPeople’s Republic of China
  8. 8.The Mental Hospital of Yunnan ProvinceKunmingPeople’s Republic of China
  9. 9.Department of Thoracic SurgerySecond Hospital of Tianjin Medical UniversityTianjinPeople’s Republic of China

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