Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Activation of p75NTR by proBDNF facilitates hippocampal long-term depression

Nature Neuroscience volume 8, pages 1069–1077 (2005)Cite this article

Abstract

Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75NTR) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75NTR, facilitates hippocampal long-term depression (LTD). Electron microscopy showed that p75NTR localized in dendritic spines, in addition to afferent terminals, of CA1 neurons. Deletion of p75NTR in mice selectively impaired the NMDA receptor–dependent LTD, without affecting other forms of synaptic plasticity. p75NTR−/− mice also showed a decrease in the expression of NR2B, an NMDA receptor subunit uniquely involved in LTD. Activation of p75NTR by proBDNF enhanced NR2B-dependent LTD and NR2B-mediated synaptic currents. These results show a crucial role for proBDNF-p75NTR signaling in LTD and its potential mechanism, and together with the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBDNF and mature BDNF.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Intact presynaptic properties in CA1 synapses of p75NTR−/− mice.
Figure 2: Selective deficit for NMDA receptor–dependent LTD in p75NTR−/− mice.
Figure 3: Localization of p75NTR immunoreactivity in mouse hippocampus.
Figure 4: Electron microscopic localization of p75NTR immunoreactivity in CA1 region of the p75NTR+/+ mouse.
Figure 5: Enhancement of NMDA receptor–dependent LTD by proBDNF.
Figure 6: Enhancement of hippocampal LTD by proBNDF is mediated by p75NTR and NR2B.
Figure 7: Relationship between p75NTR and NR2B at hippocampal CA1 synapse.
Figure 8: Attenuated levels of NR2B expression in p75NTR−/− mice.

Similar content being viewed by others

References

  1. Lu, B. BDNF and activity-dependent synaptic modulation. Learn. Mem. 10, 86–98 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Poo, M.M. Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2, 24–32 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Korte, M. et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA 92, 8856–8860 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Figurov, A., Pozzo-Miller, L., 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 

  5. Patterson, S.L. et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16, 1137–1145 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Lessmann, V., Gottmann, K. & Malcangio, M. Neurotrophin secretion: current facts and future prospects. Prog. Neurobiol. 69, 341–374 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Lu, B. Pro-region of neurotrophins: role in synaptic modulation. Neuron 39, 735–738 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Mowla, S.J. et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J. Biol. Chem. 276, 12660–12666 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Seidah, N.G., Benjannet, S., Pareek, S., Chretien, M. & Murphy, R.A. Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett. 379, 247–250 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Kaplan, D.R. & Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Huang, E.J. & Reichardt, L.F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, R., Kermani, P., Teng, K.K. & Hempstead, B.L. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945–1948 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Chao, M.V. & Bothwell, M. Neurotrophins: to cleave or not to cleave. Neuron 33, 9–12 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Ibanez, C.F. Jekyll-Hyde neurotrophins: the story of proNGF. Trends Neurosci. 25, 284–286 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Nykjaer, A. et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843–848 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Beattie, M.S. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36, 375–386 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Harrington, A.W. et al. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc. Natl. Acad. Sci. USA 101, 6226–6230 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 

  19. Dechant, G. & Barde, Y.A. The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat. Neurosci. 5, 1131–1136 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Barker, P.A. p75NTR is positively promiscuous: novel partners and new insights. Neuron 42, 529–533 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Lou, H. et al. Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase e. Neuron 45, 245–255 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Chen, Z.-Y. et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type bdnf in neurosecretory cells and cortical neurons. J. Neurosci. 24, 4401–4411 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, K.F. et al. Targeted mutation of the gene encoding the low affinity NGF repector p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–749 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Massey, P.V. et al. Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J. Neurosci. 24, 7821–7828 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cabin, D.E. et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J. Neurosci. 22, 8797–8807 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mischel, P.S. et al. The extracellular domain of p75NTR is necessary to inhibit neurotrophin-3 signaling through TrkA. J. Biol. Chem. 276, 11294–11301 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Oliet, S.H., Malenka, R.C. & Nicoll, R.A. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neuron 18, 969–982 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Hempstead, B.L. The many faces of p75NTR. Curr. Opin. Neurobiol. 12, 260–267 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Kemp, N. & Bashir, Z.I. Induction of LTD in the adult hippocampus by the synaptic activation of AMPA/kainate and metabotropic glutamate receptors. Neuropharmacology 38, 495–504 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Mulkey, R.M. & Malenka, R.C. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron 9, 967–975 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Dudek, S.M. & Bear, M.F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc. Natl. Acad. Sci. USA 89, 4363–4367 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dougherty, K.D. & Milner, T.A. Cholinergic septal afferent terminals preferentially contact neuropeptide Y-containing interneurons compared to parvalbumin-containing interneurons in the rat dentate gyrus. J. Neurosci. 19, 10140–10152 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ikegaya, Y., Ishizaka, Y. & Matsuki, N. BDNF attenuates hippocampal LTD via activation of phospholipase C: implications for a vertical shift in the frequency-response curve of synaptic plasticity. Eur. J. Neurosci. 16, 145–148 (2002).

    Article  PubMed  Google Scholar 

  37. Kirkwood, A., Rozas, C., Kirkwood, J., Perez, F. & Bear, M.F. Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine. J. Neurosci. 19, 1599–1609 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wright, J.W., Alt, J.A., Turner, G.D. & Krueger, J.M. Differences in spatial learning comparing transgenic p75 knockout, New Zealand Black, C57BL/6, and Swiss Webster mice. Behav. Brain Res. 153, 453–458 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Peterson, D.A., Dickinson-Anson, H.A., Leppert, J.T., Lee, K.F. & Gage, F.H. Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. J. Comp. Neurol. 404, 1–20 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Rosch, 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 

  41. Bandtlow, C. & Dechant, G. From cell death to neuronal regeneration, effects of the p75 neurotrophin receptor depend on interactions with partner subunits. Sci. STKE 2004, pe24 (2004).

    PubMed  Google Scholar 

  42. Davis, R.J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. O'Neill, L.A. & Kaltschmidt, C. NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 20, 252–258 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Yan, Q. & Johnson, E.M., Jr. An immunohistochemical study of the nerve growth factor receptor in developing rats. J. Neurosci. 8, 3481–3498 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Van der Zee, C.E., Ross, G.M., Riopelle, R.J. & Hagg, T. Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice. Science 274, 1729–1732 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Lu, B., Pang, P.T. & Woo, N.H. The yin and yang of neurotrophin action. Nat. Rev. Neurosci. (in the press).

  47. Lee, K.F., Bachman, K., Landis, S. & Jaenisch, R. Dependence of the p75 innervation of some sympathetic targets. Science 263, 1447–1449 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Dougherty, K.D. & Milner, T.A. p75NTR immunoreactivity in the rat dentate gyrus is mostly within presynaptic profiles but is also found in some astrocytic and postsynaptic profiles. J. Comp. Neurol. 407, 77–91 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Peters, A., Palay, S.L. & Webster, H.deF. The Fine Structure of the Nervous System (Oxford University Press, New York, 1991).

    Google Scholar 

  50. Ji, Y., Pang, P.T., Feng, L. & Lu, B. Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat. Neurosci. 8, 164–172 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by funds from National Institute of Child Health and Human Development intramural program (to B.L.), and US National Institutes of Health grants NS30658 (to B.L.H.) and HL18974 (to T.A.M.). N.H.W. is supported by fellowships from Alberta Heritage Foundation for Medical Research and Natural Sciences and Engineering Research Council of Canada. We would like to thank K. Sakata, J. Chang and K. Pelkey for advice and assistance. We also thank L. Tessarollo for providing p75NTR−/− mice and L. Reichardt for the p75NTR-blocking REX antibody.

Author information

Authors and Affiliations

  1. Section on Neural Development and Plasticity, LCSN, NICHD, Porter Neuroscience Research Center, 35 Lincoln Drive, Bethesda, 20892-3714, Maryland, USA

    Newton H Woo, Cristina Chiaruttini, Petti T Pang & Bai Lu

  2. Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, 10021, New York, USA

    Henry K Teng, Chia-Jen Siao & Barbara L Hempstead

  3. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 411 East 69th Street, New York, 10021, New York, USA

    Teresa A Milner

Authors
  1. Newton H Woo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henry K Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chia-Jen Siao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cristina Chiaruttini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Petti T Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Teresa A Milner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Barbara L Hempstead
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bai Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bai Lu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Hippocampal LTD induced by LFS is NMDA receptor-dependent. (PDF 177 kb)

Supplementary Fig. 2

Ultrastructural localization of p75NTR immunoreactivity in the hippocampus of p75NTR+/+ (i.e., Ngfr+/+) mice. (PDF 4149 kb)

Supplementary Fig. 3

proBDNF does not affect hippocampal LTP. (PDF 101 kb)

Supplementary Fig. 4

Attenuated expression of NR2B in area CA1 of p75NTR−/− (i.e., Ngfr−/−) hippocampal slices. (PDF 2513 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Woo, N., Teng, H., Siao, CJ. et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8, 1069–1077 (2005). https://doi.org/10.1038/nn1510

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1510

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing