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

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Abstract

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.

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Funding

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

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Authors and Affiliations

  1. Department of Pathology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China

    C. R. Yang, X. Y. Zhang, R. Liang & M. Yu

  2. School of Pharmacology and Medical Science, University of South Australia, Adelaide, 5000, Australia

    F. H. Zhou & X. F. Zhou

  3. Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, People’s Republic of China

    C. R. Yang & D. Ming

  4. Tianjin Mental Health Center, Tianjin, People’s Republic of China

    Y. Liu & J. Y. Du

  5. Department of Neurology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China

    F. Q. Zhang

  6. Department of Clinical Laboratory, Qingdao Central Hospital, Qingdao, Shandong Province, People’s Republic of China

    X. F. Mu

  7. Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, People’s Republic of China

    F. Li

  8. The Mental Hospital of Yunnan Province, Kunming, Yunnan Province, People’s Republic of China

    L. Zhou

  9. Department of Thoracic Surgery, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China

    F. J. Meng & S. Wang

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  1. C. R. Yang
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Correspondence to D. Ming or X. F. Zhou.

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Yang, C.R., Zhang, X.Y., Liu, Y. et al. Antidepressant Drugs Correct the Imbalance Between proBDNF/p75NTR/Sortilin and Mature BDNF/TrkB in the Brain of Mice with Chronic Stress. Neurotox Res 37, 171–182 (2020). https://doi.org/10.1007/s12640-019-00101-2

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