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.

  • Review Article
  • Published:

Neurotrophins and their receptors: A convergence point for many signalling pathways

Key Points

  • Neurotrophins are most often associated with the promotion of neuronal growth and survival, but their influence on brain function is significantly broader — they are also involved in plastic and pathological processes.

  • Clues to the multiple functions of neurotrophins come from the study of mutant animals. In particular, as knocking out any neurotrophin gene leads to a lethal phenotype, the analysis of heterozygous mice has pointed to roles for the neurotrophins in locomotor and feeding behaviours.

  • The fact that the actions of the neurotrophins depend on two receptor classes — the Trk receptors and p75 — significantly increases the degrees of freedom for neurotrophin signalling in terms of specificity, affinity and downstream signalling pathways.

  • Neurotrophins have significant direct effects on synaptic transmission, plasticity and their possible behavioural correlates. However, the downstream mechanisms that mediate these effects are not completely understood. Several signalling pathways have been put forward as candidates, and recently ion channels have joined the list of potential effectors of the synaptic actions of neurotrophins.

  • Transactivation of neurotrophin receptors by G protein-coupled receptors has emerged as a new theme in the biology of neurotrophin function. Although the precise role of this transactivation is unknown, one possibility is that it adds a safety factor that might protect neurons from death in the absence of neurotrophins.

  • Neurotrophin receptors, particularly p75, might have an important role in the control of axonal regeneration, as they act as co-receptors for Nogo, a protein that is known to inhibit axonal growth. In addition, the neurotrophins can modulate the response of growth cones to guidance molecules such as semaphorins.

  • There is some genetic evidence that points to a specific contribution of the neurotrophins to psychiatric disease. Specifically, polymorphisms of brain-derived neurotrophic factor have been linked to depression, bipolar disorders and schizophrenia.

Abstract

The neurotrophins are a family of proteins that are essential for the development of the vertebrate nervous system. Each neurotrophin can signal through two different types of cell surface receptor — the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. Given the wide range of activities that are now associated with neurotrophins, it is probable that additional regulatory events and signalling systems are involved. Here, I review recent findings that neurotrophins, in addition to promoting survival and differentiation, exert various effects through surprising interactions with other receptors and ion channels.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Models of Trk and p75 receptor activation.
Figure 2: Neurotrophin receptor signalling.
Figure 3: Examples of ion channel interactions with Trk neurotrophin receptors.
Figure 4: Transactivation of receptor tyrosine kinases.
Figure 5: Neurotrophins and p75 undergo site-specific cleavages.

Similar content being viewed by others

References

  1. McAllister, A., Katz, L. & Lo, D. Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22, 295–318 (1999).

    CAS  PubMed  Google Scholar 

  2. Poo, M. -M. Neurotrophins as synaptic modulators. Nature Rev. Neurosci. 2, 24–31 (2001).

    CAS  Google Scholar 

  3. Huang, E. & Reichardt, L. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Chao, M. V. & Hempstead, B. L. p75 and trk: a two-receptor system. Trends Neurosci. 18, 321–326 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Dechant, G. & Barde, Y. -A. The neurotrophin receptor p75NTR: novel functions and implications for diseases of the nervous system. Nature Neurosci. 5, 1131–1136 (2002).

    CAS  PubMed  Google Scholar 

  7. Gall, C. & Isackson, P. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 245, 758–761 (1989).

    CAS  PubMed  Google Scholar 

  8. Blochl, A. & Thoenen, H. Characterization of nerve growth factor release from hippocampal neurons: evidence for a constitutive and an unconventional sodium-dependent regulated pathway. Eur. J. Neurosci. 7, 1220–1228 (1995).

    CAS  PubMed  Google Scholar 

  9. Wang, X. H. & Poo, M. -M. Potentiation of developing synapses by postsynaptic release of NT-4. Neuron 19, 825–835 (1997).

    CAS  PubMed  Google Scholar 

  10. Gall, C. Regulation of brain neurotrophin expression by physiological activity. Trends Pharmacol. Sci. 13, 401–403 (1992).

    CAS  PubMed  Google Scholar 

  11. Schoups, A., Elliott, R., Friedman, W. & Black, I. NGF and BDNF are differentially modulated by visual experience in the developing geniculocortical pathway. Brain Res. Dev. 86, 326–334 (1995).

    CAS  Google Scholar 

  12. Lein, E., Hohn, A. & Shatz, C. Dynamic regulation of BDNF and NT-3 expression during visual system development. J. Comp. Neurol. 420, 1–18 (2000).

    CAS  PubMed  Google Scholar 

  13. Kohara, K., Kitamura, A., Morishima, M. & Tsumoto, T. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. Science 291, 2419–2423 (2001).

    CAS  PubMed  Google Scholar 

  14. Balkowiec, A. & Katz, D. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J. Neurosci. 22, 10399–10407 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chen, K. et al. Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits. J. Neurosci. 17, 7288–7296 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lyons, W. E. et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc. Natl Acad. Sci. USA 96, 15239–15244 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kernie, S., Liebl, D. & Parada, L. BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19, 1290–1300 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Rios, M. et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15, 1748–1757 (2001). Profound effects on feeding and aggressive behaviours have been observed in three different lines of mice with reduced levels of BDNF. These results indicate that a partial depletion of BDNF can have a key role in regulating behavioural responses, in this case, through serotonergic abnormalities.

    CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Heymach, J. V. & Shooter, E. M. The biosynthesis of neurotrophin heterodimers by transfected mammalian cells. J. Biol. Chem. 270, 12297–12304 (1995).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

  23. Dechant, G. et al. Expression and binding characteristics of the BDNF receptor chick trkB. Development 119, 545–558 (1993).

    CAS  PubMed  Google Scholar 

  24. Mahadeo, D., Kaplan, L., Chao, M. V. & Hempstead, B. L. High affinity nerve growth factor binding displays a faster rate of association than p140(trk) binding — implications for multisubunit polypeptide receptors. J. Biol. Chem. 269, 6884–6891 (1994).

    CAS  PubMed  Google Scholar 

  25. Schropel, A., von Schack, D., Dechant, G. & Barde, Y. -A. Early expression of the nerve growth factor receptor ctrkA in chick sympathetic and sensory ganglia. Mol. Cell. Neurosci. 6, 544–556 (1995).

    CAS  PubMed  Google Scholar 

  26. Arevalo, J. et al. TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor. Mol. Cell Biol. 20, 5908–5916 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Esposito, D. et al. The cytoplasmic and transmembrane domains of the p75 and TrkA receptors regulate high affinity binding to nerve growth factor. J. Biol. Chem. 276, 32687–32695 (2001).

    CAS  PubMed  Google Scholar 

  28. Hempstead, B. L., Martin-Zanca, D., Kaplan, D. R., Parada, L. F. & Chao, M. V. High-affinity NGF binding requires co-expression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350, 678–683 (1991).

    CAS  PubMed  Google Scholar 

  29. Benedetti, M., Levi, A. & Chao, M. V. Differential expression of nerve growth factor receptors leads to altered binding affinity and neurotrophin responsiveness. Proc. Natl Acad. Sci. USA 90, 7859–7863 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bibel, M., Hoppe, E. & Barde, Y. Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. EMBO J. 18, 616–622 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Baloh, R., Enomoto, H., Johnson, E. & Milbrandt, J. The GDNF family ligands and receptors — implications for neural development. Curr. Opin. Neurobiol. 10, 103–110 (2000).

    CAS  PubMed  Google Scholar 

  32. Ginty, D. & Segal, R. Retrograde neurotrophin signaling: Trk-ing along the axon. Curr. Opin. Neurobiol. 12, 268–274 (2002).

    CAS  PubMed  Google Scholar 

  33. Grimes, M., Beattie, E. & Mobley, W. A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA. Proc. Natl Acad. Sci. USA 94, 9909–9914 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Patapoutian, A. & Reichardt, L. Trk receptors: mediators of neurotrophin action. Curr. Opin. Neurobiol. 11, 272–280 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  36. Roux, P. & Barker, P. Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol. 67, 203–233 (2002).

    CAS  PubMed  Google Scholar 

  37. Lonze, B. & Ginty, D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).

    CAS  PubMed  Google Scholar 

  38. York, R. et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392, 622–626 (1998).

    CAS  PubMed  Google Scholar 

  39. Majdan, M. & Miller, F. Neuronal life and death decisions: functional antagonism between the Trk and p75 neurotrophin receptors. Int. J. Dev. Neurosci. 17, 153–161 (1999).

    CAS  PubMed  Google Scholar 

  40. Dowling, P. et al. Upregulated p75NTR neurotrophin receptor on glial cells in MS plaques. Neurology 53, 1676–1682 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Harrington, A. W., Kim, J. Y. & Yoon, S. O. Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis. J. Neurosci. 22, 156–166 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Khursigara, G. et al. A pro-survival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor interacting protein 2. J. Neurosci. 21, 5854–5863 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. DeFreitas, M., McQuillen, P. & Shatz, C. A novel p75NTR signaling pathway promotes survival, not death, of immunopurified neocortical subplate neurons. J. Neurosci. 21, 5121–5129 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lee, R., Kermani, P., Teng, K. & Hempstead, B. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945–1948 (2001). The precursor forms of neurotrophins have been implicated in the folding and processing of the mature proteins. This paper indicates that the pro-sequence of NGF preferentially binds to the p75 receptor.

    CAS  PubMed  Google Scholar 

  47. Chao, M. V. Growth factor signaling: where is the specificity? Cell 68, 995–997 (1992).

    CAS  PubMed  Google Scholar 

  48. Lohof, A. M., Ip, N. & Poo, M. -M. Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 363, 350–353 (1993).

    CAS  PubMed  Google Scholar 

  49. Kang, H. & Schuman, E. M. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267, 1658–1662 (1995).

    CAS  PubMed  Google Scholar 

  50. Levine, E. S., Dreyfus, C. F., Black, I. B. & Plummer, M. R. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc. Natl Acad. Sci. USA 92, 8074–8077 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Xie, C. et al. Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4. Proc. Natl Acad. Sci. USA 97, 8116–8121 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Korte, M. et al. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc. Natl Acad. Sci. USA 93, 12547–12552 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Schuman, E. Neurotrophin regulation of synaptic transmission. Curr. Opin. Neurobiol. 9, 105–109 (1999).

    CAS  PubMed  Google Scholar 

  54. Schinder, A. & Poo, M. -M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 23, 639–645 (2000).

    CAS  PubMed  Google Scholar 

  55. Yang, F. et al. PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nature Neurosci. 4, 19–28 (2001).

    CAS  PubMed  Google Scholar 

  56. Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999).

    CAS  PubMed  Google Scholar 

  57. Minichiello, L. et al. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36, 121–137 (2002).

    CAS  PubMed  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. von Schack, D. et al. Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nature Neurosci. 4, 977–978 (2001).

    CAS  PubMed  Google Scholar 

  60. Dalva, M. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000).

    CAS  PubMed  Google Scholar 

  61. Grunwald, I. et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32, 1027–1040 (2001).

    CAS  PubMed  Google Scholar 

  62. Henderson, J. et al. The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 1041–1056 (2001).

    CAS  PubMed  Google Scholar 

  63. Takasu, M., Dalva, M., Zigmond, R. & Greenberg, M. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491–495 (2002).

    CAS  PubMed  Google Scholar 

  64. Montell, C., Birnbaumer, L. & Flockerzi, V. The TRP channels, a remarkably functional family. Cell 108, 595–598 (2002).

    CAS  PubMed  Google Scholar 

  65. Li, H., Xu, X. & Montell, C. Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron 24, 261–273 (1999). BDNF binding to TrkB produced a rapid influx of cations through TRPC3 that was dependent on activation of phospholipase C. An interaction between TrkB receptors and TRPC3 ion channels was observed, indicating that ion channels might be closely associated with receptor tyrosine kinases.

    CAS  PubMed  Google Scholar 

  66. Caterina, M. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    CAS  PubMed  Google Scholar 

  67. Shu, X. & Mendell, L. Neurotrophins and hyperalgesia. Proc. Natl Acad. Sci. USA 96, 7693–7696 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Chuang, H. -h. et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957–962 (2001). This study shows that the capsaicin (TRPV1) receptor is activated through NGF binding to TrkA receptors. The interaction between a receptor tyrosine kinase and a pain-related channel provides a mechanism for the ability of sensory neurons to respond to NGF-mediated heat sensitivity and also points to a mechanism for the heightened hyperalgesia that is observed after administration of neurotrophins in clinical trials of neurodegenerative diseases.

    CAS  PubMed  Google Scholar 

  69. Johagen, M. et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement. Geriat. Cogn. 9, 246–257 (1998).

    Google Scholar 

  70. Thoenen, H. & Sendtner, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nature Neurosci. 5, S1046–S1050 (2002).

    Google Scholar 

  71. Lin, S. et al. BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities. Brain Res. Mol. Brain Res. 55, 20–27 (1998).

    CAS  PubMed  Google Scholar 

  72. Tucker, K. & Fadool, D. Neurotrophin modulation of voltage-gated potassium channels in rat through TrkB receptors is time and sensory experience dependent. J. Physiol. (Lond.) 542, 413–429 (2002).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  74. Gottschalk, W., Pozzo-Miller, L., Figurov, A. & Lu, B. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J. Neurosci. 18, 6830–6839 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Xu, B. et al. The role of brain-derived neurotrophic factors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J. Neurosci. 20, 6888–6897 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kovalchuk, Y., Hanse, E., Kafitz, K. & Konnerth, A. Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295, 1729–1734 (2002).

    CAS  PubMed  Google Scholar 

  77. Balkowiec, A., Kunze, D. & Katz, D. Brain-derived neurotrophic factor acutely inhibits AMPA-mediated currents in developing sensory relay neurons. J. Neurosci. 20, 1904–1911 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Carroll, R., Beattie, E., von Zastrow, M. & Malenka, R. Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev. Neurosci. 2, 315–324 (2001).

    CAS  Google Scholar 

  79. Blum, R., Kafitz, K. & Konnerth, A. Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Nature 419, 687–693 (2002).

    CAS  PubMed  Google Scholar 

  80. Kafitz, K., Rose, C., Thoenen, H. & Konnerth, A. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 401, 918–921 (1999). A remarkably rapid response of a sodium channel by BDNF treatment is documented in references 79 and 80.

    CAS  PubMed  Google Scholar 

  81. Choi, D. -Y., Toledo-Aral, J., Segal, R. & Halegoua, S. Sustained signaling by phospholipase C-γ mediates nerve growth factor-triggered gene expression. Mol. Cell Biol. 21, 2695–2705 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Toledo-Aral, J., Brehm, P., Halegoua, S. & Mandel, G. A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction. Neuron 14, 607–611 (1995).

    CAS  PubMed  Google Scholar 

  83. Arevalo, J. et al. A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation. Oncogene 20, 1229–1234 (2001).

    CAS  PubMed  Google Scholar 

  84. Daub, H., Weiss, F. U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein coupled receptors. Nature 379, 557–560 (1996).

    CAS  PubMed  Google Scholar 

  85. Luttrell, L., Daaka, Y. & Lefkowitz, R. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr. Opin. Cell Biol. 11, 177–183 (1999).

    CAS  PubMed  Google Scholar 

  86. Lee, F. & Chao, M. Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc. Natl Acad. Sci. USA 98, 3555–3560 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lee, F. S., Ragagopal, R., Kim, A. H., Chang, P. & Chao, M. V. Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J. Biol. Chem. 277, 9096–9102 (2002).

    CAS  PubMed  Google Scholar 

  88. Takei, N. et al. Pituitary adenylate cyclase-activating polypeptide promotes the survival of basal forebrain cholinergic neurons in vitro and in vivo: comparison with effects of nerve growth factor. Eur. J. Neurosci. 12, 2273–2280 (2000).

    CAS  PubMed  Google Scholar 

  89. Williams, L. R. et al. Continuous infusion of NGF prevents basal forebrain neuronal death after fimbria fornix transection. Proc. Natl Acad. Sci. USA 83, 9231–9235 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kotecha, S. et al. A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 35, 1111–1122 (2002).

    CAS  PubMed  Google Scholar 

  91. Otto, C. et al. Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice. J. Neurosci. 21, 5520–5527 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Hashimoto, H., Shintani, N. & Baba, A. Higher brain functions of PACAP and a homologous Drosophila memory gene amnesiac: insights from knockouts and mutants. Biochem. Biophys. Res. Commun. 297, 427–432 (2002).

    CAS  PubMed  Google Scholar 

  93. Ledent, C. et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388, 674–678 (1997).

    CAS  PubMed  Google Scholar 

  94. Airaksinen, M. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nature Rev. Neurosci. 3, 383–394 (2002).

    CAS  Google Scholar 

  95. Tsui-Pierchala, B., Milbrandt, J. & Johnson, E. NGF utilizes c-Ret via a novel GFL-independent, inter-RTK signaling mechanism to maintain the trophic status of mature sympathetic neurons. Neuron 33, 261–273 (2002).

    CAS  PubMed  Google Scholar 

  96. Duman, R., Heninger, G. & Nestler, E. A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54, 597–606 (1997).

    CAS  PubMed  Google Scholar 

  97. Cai, D., Shen, Y., DeBellard, M., Tang, S. & Filbin, M. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101 (1999).

    CAS  PubMed  Google Scholar 

  98. Luo, Y., Raible, D. & Raper, J. Collapsin, a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993).

    CAS  PubMed  Google Scholar 

  99. Tuttle, R. & O'Leary, D. Neurotrophins rapidly modulate growth cone response in the axon guidance molecule, collapsin-1. Mol. Cell. Neurosci. 11, 1–8 (1998).

    CAS  PubMed  Google Scholar 

  100. Dontchev, V. & Letourneau, P. Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. J. Neurosci. 22, 6659–6669 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Fournier, A., GrandPre, T. & Strittmatter, S. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001).

    CAS  PubMed  Google Scholar 

  102. Wang, K. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).

    CAS  PubMed  Google Scholar 

  103. Liu, B., Fournier, A., GrandPre, T. & Strittmatter, S. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297, 1190–1193 (2002).

    CAS  PubMed  Google Scholar 

  104. Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo-66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290 (2002).

    CAS  PubMed  Google Scholar 

  105. Wang, K., Kim, J., Sivasankaran, R., Segal, R. & He, Z. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002).

    CAS  PubMed  Google Scholar 

  106. Wong, S. et al. A p75NTR and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nature Neurosci. 5, 1302–1308 (2002). These papers merge neurotrophin receptor signalling to inhibition of regeneration in the CNS through the actions of three unrelated proteins — Nogo, p75 and MAG.

    CAS  PubMed  Google Scholar 

  107. Yamashita, T., Higuchi, H. & Tohyama, M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J. Cell Biol. 157, 565–570 (2002). An important link is made between the ability of MAG to block axonal growth and Rho activity through the p75 receptor. The results led to the experiments showing that the p75 and Nogo receptors act in a complex.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Yamashita, T., Tucker, K. & Barde, Y. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593 (1999).

    CAS  PubMed  Google Scholar 

  109. Walsh, G., Krol, K., Crutcher, K. & Kawaja, M. Enhanced neurotrophin-induced axon growth in myelinated portions of the CNS in mice lacking the p75 neurotrophin receptor. J. Neurosci. 19, 4155–4168 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Dobrowsky, R. T. & Carter, B. D. p75 neurotrophin receptor signaling: mechanisms for neurotrophic modulation of cell stress? J. Neurosci. Res. 61, 237–243 (2000).

    CAS  PubMed  Google Scholar 

  111. Cosgaya, J. & Shooter, E. Binding of nerve growth factor to its p75 receptor in stressed cells induces selective IκB-β degradation and NF-κB nuclear translocation. J. Neurochem. 79, 391–399 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  113. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Sen, S. et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28, 397–401 (2003).

    CAS  PubMed  Google Scholar 

  115. Egan, M. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269 (2003). This study is the first to show that a human polymorphism in BDNF is associated with memory deficits. A single amino acid variation in the pro-domain of BDNF accounts for the ability of BDNF to undergo proper secretion.

    CAS  PubMed  Google Scholar 

  116. Ventriglia, M. et al. Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol. Psychiatry 7, 136–137 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Ueyama, T. et al. Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain. Neurosci. Res. 28, 103–110 (1997).

    CAS  PubMed  Google Scholar 

  119. Shirayama, Y., Chen, A., Nakagawa, S., Russell, D. & Duman, R. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251–3261 (2002). Administration of exogenous BDNF exerted profound positive effects in forced swim and learned helplessness assays, indicating that BDNF signalling might be related to depression.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Elliott, T. & Shadbolt, N. Competition for neurotrophic factors: mathematical analysis. Neural Comput. 10, 1939–1981 (1998).

    CAS  PubMed  Google Scholar 

  121. Crowley, C. et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76, 1001–1012 (1994).

    CAS  PubMed  Google Scholar 

  122. Bartoletti, A. et al. Heterozygous knock-out mice for brain-derived neurotrophic factor show a pathway-specific impairment of long-term potentiation but normal critical period for monocular deprivation. J. Neurosci. 22, 10072–10077 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Dluzen, D. et al. Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/− BDNF mutant mice. Exp. Neurol. 170, 121–128 (2001).

    CAS  PubMed  Google Scholar 

  124. Carroll, P., Lewin, G., Koltzenburg, M., Toyka, K. & Thoenen, H. A role for BDNF in mechanosensation. Nature Neurosci. 1, 42–46 (1998).

    CAS  PubMed  Google Scholar 

  125. Ernfors, P., Lee, K. F. & Jaenisch, R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150 (1994).

    CAS  PubMed  Google Scholar 

  126. Bianchi, L. et al. Degeneration of vestibular neurons in late embryogenesis of both heterozygous and homozygous BDNF null mutant mice. Development 122, 1965–1973 (1996).

    CAS  PubMed  Google Scholar 

  127. Elmer, E. et al. Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice. Exp. Neurol. 145, 93–103 (1997).

    CAS  PubMed  Google Scholar 

  128. Donovan, M., Hahn, R., Tessarollo, L. & Hempstead, B. Neurotrophin-3 is required for mammalian cardiac development: identification of an essential nonneuronal neurotrophin function. Nature Genet. 14, 210–213 (1996).

    CAS  PubMed  Google Scholar 

  129. Airaksinen, M. et al. Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation. Neuron 16, 287–295 (1996).

    CAS  PubMed  Google Scholar 

  130. Ernfors, P., Lee, K. -F., Kucera, J. & Jaenisch, R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 77, 503–512 (1994).

    CAS  PubMed  Google Scholar 

  131. DiStefano, P., Chelsea, D., Schick, C. & McKelvy, J. Involvement of a metalloprotease in low-affinity nerve growth factor receptor truncation: inhibition of truncation in vitro and in vivo. J. Neurosci. 13, 2405–2414 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Schecterson, L., Kanning, K., Hudson, M. & Bothwell, M. The neurotrophin receptor p75 is cleaved by regulated intramembranous proteolysis. Soc. Neurosci. Abstr. 27, 822.10 (2002). Intramembranous cleavage of Notch, the amyloid precursor protein and ErbB4 receptors generates intracellular cytoplasmic fragments that produce marked changes in signalling and transcriptional activities. The cleavage of p75 by a γ-secretase reveals a new mechanism for transmitting neurotrophin signals from the cell surface to intracellular locations.

    Google Scholar 

  133. Brown, M., Ye, J., Rawson, R. & Goldstein, J. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391–398 (2000).

    CAS  PubMed  Google Scholar 

  134. Fahnestock, M., Michalski, B., Xu, B. & Coughlin, M. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease. Mol. Cell. Neurosci. 18, 210–220 (2001).

    CAS  PubMed  Google Scholar 

  135. Cosgaya, J. M., Chan, J. R. & Shooter, E. M. The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298, 1245–1248 (2002).

    CAS  PubMed  Google Scholar 

  136. Wu, C., Lai, C. F. & Mobley, W. C. Nerve growth factor activates persistent Rap1 signaling in endosomes. J. Neurosci. 21, 5406–5416 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Lee, F., Rajagopal, R., Kim, A., Chang, P. & Chao, M. Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J. Biol. Chem. 277, 9096–9102 (2002).

    CAS  PubMed  Google Scholar 

  138. Chen, M. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monclonal antibody IN-1. Nature 403, 434–439 (2000).

    CAS  PubMed  Google Scholar 

  139. Ernfors, P., Henschen, A., Olson, L. & Persson, H. Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 2, 1605–1613 (1989).

    CAS  PubMed  Google Scholar 

  140. Koliatsos, V., Crawford, T. & Price, D. Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons. Brain Res. 549, 297–304 (1991).

    CAS  PubMed  Google Scholar 

  141. Hayes, R., Wiley, R. & Armstrong, D. Induction of nerve growth factor receptor (p75NGFr) mRNA within hypoglossal motoneurons following axonal injury. Brain Res. Mol. Brain Res. 15, 291–297 (1992).

    CAS  PubMed  Google Scholar 

  142. Martinez-Murillo, R., Fernandez, A., Bentura, M. & Rodrigo, J. Subcellular localization of low-affinity nerve growth factor receptor-immunoreactive protein in adult rat Purkinje cells following traumatic injury. Exp. Brain Res. 119, 47–57 (1998).

    CAS  PubMed  Google Scholar 

  143. Friedman, W. Neurotrophins induce death of hippocampal neurons via the p75 receptor. J. Neurosci. 20, 6340–6346 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Kokaia, Z., Andsberg, G., Martinez-Serrano, A. & Lindvall, O. Focal cerebral ischemia in rats induces expression of p75 neurotrophin receptor in resistant striatal cholinergic neurons. Neuroscience 84, 1113–1125 (1998).

    CAS  PubMed  Google Scholar 

  145. Park, J., Lee, J., Sato, T. & Koh, J. Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat. J. Neurosci. 20, 9096–9103 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Mufson, E. & Kordower, J. Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer's disease. Proc. Natl Acad. Sci. USA 89, 569–573 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lemke, G. & Chao, M. V. Axons regulate Schwann cell expression of major myelin and NGF receptor genes. Development 102, 499–504 (1988).

    CAS  PubMed  Google Scholar 

  148. Taniuchi, M., Clark, H., Schweitzer, J. & Johnson, E. Expression of nerve growth factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties. J. Neurosci. 8, 664–681 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Chang, A., Nishiyama, A., Peterson, J., Prineas, J. & Trapp, B. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Calza, L., Giardino, L., Pozza, M., Micera, A. & Aloe, L. Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc. Natl Acad. Sci. USA 94, 3368–3373 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Nataf, S. et al. Low affinity NGF receptor expression in the central nervous system during experimental allergic encephalomyelitis. J. Neurosci. Res. 52, 83–92 (1998).

    CAS  PubMed  Google Scholar 

  152. Hu, X. -Y. et al. Increased p75NTR expression in hippocampal neurons containing hyperphosphorylated τ in Alzheimer patients. Exp. Neurol. 178, 104–111 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The assistance of Albert Kim is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

Swiss-Prot

BDNF

CREB

GDNF

JNK

Kv1.3

MAG

Nav1.9

NF-κB

NGF

Nogo

PACAP

Semaphorin 3A

Shc

TrkA

TrkB

TrkC

Tumour necrosis factor

OMIM

Alzheimer disease

Glossary

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. LTP is most often studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

APOPTOSIS

The process of programmed cell death, characterized by distinctive morphological changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA.

LIGHT/DARK EXPLORATION TEST

This test depends on the natural tendency of rodents to explore the environment in the absence of a threat and to retreat to an enclosed area when fearful. The animals are placed in an apparatus that has a dark and an illuminated compartment. Reduced exploration of the bright compartment and a reduced number of transitions between compartments are commonly interpreted as measures of anxiety.

FURIN

An endopeptidase with specificity for the consensus sequence Arg-X-Lys/Arg-Arg.

KINDLING

An experimental model of epilepsy in which an increased susceptibility to seizures arises after daily focal stimulation of specific brain areas (for example, the amygdala) — stimulation that does not reach the threshold to elicit a seizure by itself.

CONDITIONAL MUTATION

A mutation that can be selectively targeted to specific organs (or cell types within an organ) or induced at a specific developmental stage.

POLYMORPHISM

The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.

LEARNED HELPLESSNESS

A commonly used model of depression in which animals are exposed to inescapable shock and subsequently tested for deficits in learning a shock-avoidance task. Learned helplessness is a rare example in which, rather than working from the psychiatric disorder to the model, the behavioural effect was originally discovered in experimental animals (dogs) and later invoked to explain depression.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chao, M. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nat Rev Neurosci 4, 299–309 (2003). https://doi.org/10.1038/nrn1078

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1078

This article is cited by

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