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New insights into BDNF function in depression and anxiety

Nature Neuroscience volume 10, pages 1089–1093 (2007)Cite this article

Abstract

The 'neurotrophin hypothesis of depression' is based largely on correlations between stress or antidepressant treatment and down- or upregulation, respectively, of brain-derived neurotrophic factor (BDNF). Genetic disruption of the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB, does not seem to cause depressive behaviors, but does hamper the effect of antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the sole mediator of depression or anxiety. Advances in BDNF cell biology, including its transcription through multiple promoters, trafficking and secretion, may provide new insights into its role in mood disorders. Moreover, as the precursor proBDNF and the mature protein mBDNF can elicit opposite effects on cellular functions, the impact of proBDNF and its cleavage on mood should be considered. Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term depression might contribute to the dichotomy of BDNF actions on behaviors mediated by the brain stress and reward systems.

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References

  1. Charney, D.S. & Manji, H.K. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci. STKE [online] 2004, re5 (2004).

    Google Scholar 

  2. Duman, R.S. & Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 1116–1127 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Dias, B.G., Banerjee, S.B., Duman, R.S. & Vaidya, V.A. Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology 45, 553–563 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Russo-Neustadt, A.A., Beard, R.C., Huang, Y.M. & Cotman, C.W. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101, 305–312 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Tsankova, N.M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat. Neurosci. 9, 519–525 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Eisch, A.J. et al. Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol. Psychiatry 54, 994–1005 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Lu, B., Pang, P.T. & Woo, N.H. The yin and yang of neurotrophin action. Nat. Rev. Neurosci. 6, 603–614 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Pang, P.T. et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306, 487–491 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Woo, N.H. et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat. Neurosci. 8, 1069–1077 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. McEwen, B.S. Protective and damaging effects of stress mediators: central role of the brain. Prog. Brain Res. 122, 25–34 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Smith, M.A., Makino, S., Kvetnansky, R. & Post, R.M. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15, 1768–1777 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nibuya, M., Morinobu, S. & Duman, R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15, 7539–7547 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Siuciak, J.A., Lewis, D.R., Wiegand, S.J. & Lindsay, R.M. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol. Biochem. Behav. 56, 131–137 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Shirayama, Y., Chen, A.C., Nakagawa, S., Russell, D.S. & Duman, R.S. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251–3261 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen, B., Dowlatshahi, D., MacQueen, G.M., Wang, J.F. & Young, L.T. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol. Psychiatry 50, 260–265 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Sheline, Y.I., Gado, M.H. & Kraemer, H.C. Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).

    Article  PubMed  Google Scholar 

  18. Neves-Pereira, M. et al. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am. J. Hum. Genet. 71, 651–655 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sklar, P. et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol. Psychiatry 7, 579–593 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Zarate, C.A., Jr. et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Chao, M.V. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat. Rev. Neurosci. 4, 299–309 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Timmusk, T. et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10, 475–489 (1993).

    CAS  PubMed  Google Scholar 

  23. Liu, Q.R. et al. Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res. 1067, 1–12 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. West, A.E. et al. Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. USA 98, 11024–11031 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pattabiraman, P.P. et al. Neuronal activity regulates the developmental expression and subcellular localization of cortical BDNF mRNA isoforms in vivo. Mol. Cell. Neurosci. 28, 556–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Chen, W.G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Martinowich, K. et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302, 890–893 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Mowla, S.J. et al. Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J. Neurosci. 19, 2069–2080 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Egan, M.F. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Chen, Z.Y. et al. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J. Neurosci. 25, 6156–6166 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen, Z.Y. et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314, 140–143 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Teng, H.K. et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 25, 5455–5463 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim, J. & Hajjar, K.A. Annexin II: a plasminogen-plasminogen activator co-receptor. Front. Biosci. 7, d341–d348 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Svenningsson, P. et al. Alterations in 5–HT1B receptor function by p11 in depression-like states. Science 311, 77–80 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Zhou, X.F. et al. Distribution and localization of pro-brain-derived neurotrophic factor-like immunoreactivity in the peripheral and central nervous system of the adult rat. J. Neurochem. 91, 704–715 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Volosin, M. et al. Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins. J. Neurosci. 26, 7756–7766 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Figurov, A., Pozzo-Miller, L.D., Olafsson, P., Wang, T. & Lu, B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Zagrebelsky, M. et al. The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J. Neurosci. 25, 9989–9999 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. MacQueen, G.M. et al. Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression. Behav. Neurosci. 115, 1145–1153 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Saarelainen, T. et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J. Neurosci. 23, 349–357 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Govindarajan, A. et al. Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc. Natl. Acad. Sci. USA 103, 13208–13213 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pawlak, R. et al. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc. Natl. Acad. Sci. USA 102, 18201–18206 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Roux, P.P., Colicos, M.A., Barker, P.A. & Kennedy, T.E. p75 neurotrophin receptor expression is induced in apoptotic neurons after seizure. J. Neurosci. 19, 6887–6896 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kohen, R. et al. Gene expression profiling in the hippocampus of learned helpless and nonhelpless rats. Pharmacogenomics J. 5, 278–291 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Monteggia, L.M. et al. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol. Psychiatry 61, 187–197 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Zorner, B. et al. Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than “depressive”. Biol. Psychiatry 54, 972–982 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Ren-Patterson, R.F. et al. Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. J. Neurosci. Res. 79, 756–771 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Xu, L., Anwyl, R. & Rowan, M.J. Behavioural stress facilitates the induction of long-term depression in the hippocampus. Nature 387, 497–500 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Holderbach, R., Clark, K., Moreau, J.L., Bischofberger, J. & Normann, C. Enhanced long-term synaptic depression in an animal model of depression. Biol. Psychiatry 62, 92–100 (2006).

    Article  PubMed  Google Scholar 

  50. Rösch, H., Schweigreiter, R., Bonhoeffer, T., Barde, Y.A. & Korte, M. The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc. Natl. Acad. Sci. USA 102, 7362–7367 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors' work is supported by funds from intramural research programs of the US National Institute of Mental Health and National Institute of Child Health and Human Development.

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Authors and Affiliations

  1. Mood and Anxiety Program, National Institute of Mental Health, Building 35, Room 1C1004, 35 Convent Drive, MSC 3714, Bethesda, Maryland 20892-3714, USA.,

    Keri Martinowich & Husseini Manji

  2. Section on Neural Development & Plasticity, National Institute of Child Health and Human Development,

    Bai Lu

  3. National Institutes of Health, Building 35, Room 1C1004, 35 Convent Drive, MSC 3714, Bethesda, 20892-3714, Maryland, USA

    Bai Lu

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Martinowich, K., Manji, H. & Lu, B. New insights into BDNF function in depression and anxiety. Nat Neurosci 10, 1089–1093 (2007). https://doi.org/10.1038/nn1971

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