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Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons

Abstract

Extracellular factors may act on cells in two distinct modes: an acute increase in concentration as a result of regulated secretion, or a gradual increase in concentration when secreted constitutively or from a distant source. We found that cellular responses to brain-derived neurotrophic factor (BDNF) differed markedly depending on how BDNF was delivered. In cultured rat hippocampal neurons, acute and gradual increases in BDNF elicited transient and sustained activation of TrkB receptor and its downstream signaling, respectively, leading to differential expression of Homer1 and Arc. Transient TrkB activation promoted neurite elongation and spine head enlargement, whereas sustained TrkB activation facilitated neurite branch and spine neck elongation. In hippocampal slices, fast and slow increases in BDNF enhanced basal synaptic transmission and LTP, respectively. Thus, the kinetics of TrkB activation is critical for cell signaling and functions. This temporal dimension in cellular signaling may also have implications for the therapeutic drug design.

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Figure 1: Transient or sustained TrkB and Erk activation induced by acute or gradual BDNF stimulation.
Figure 2: Differential expression of Homer1 and Arc by acute and gradual modes of BDNF stimulation.
Figure 3: Differential effects of acute and gradual modes on neurite growth of young neurons.
Figure 4: Acute and gradual modulation of dendritic spine growth of mature neurons.
Figure 5: Differential signaling of fast and slow BDNF stimulation in hippocampal slices.
Figure 6: Differential physiological effects of fast and slow BDNF stimulation in hippocampal slices.
Figure 7: Differential regulation of NMDAR EPSCs and AMPAR/NMDAR ratio by fast and slow BDNF application.

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References

  1. Marshall, C.J. Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Mei, L. & Xiong, W.C. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat. Rev. Neurosci. 9, 437–452 (2008).

    Article  CAS  Google Scholar 

  4. Segal, R.A. Selectivity in neurotrophin signaling: theme and variations. Annu. Rev. Neurosci. 26, 299–330 (2003).

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. 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  Google Scholar 

  7. Huang, Y.Z. et al. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26, 443–455 (2000).

    Article  CAS  Google Scholar 

  8. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Traverse, S., Gomez, N., Paterson, H., Marshall, C. & Cohen, P. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem. J. 288, 351–355 (1992).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Canossa, M. et al. Neurotrophin release by neurotrophins: implications for activity-dependent neuronal plasticity. Proc. Natl. Acad. Sci. USA 94, 13279–13286 (1997).

    Article  CAS  Google Scholar 

  13. Goodman, L.J. et al. Regulated release and polarized localization of brain-derived neurotrophic factor in hippocampal neurons. Mol. Cell. Neurosci. 7, 222–238 (1996).

    Article  CAS  Google Scholar 

  14. Griesbeck, O. et al. Are there differences between the secretion characteristics of NGF and BDNF? Implications for the modulatory role of neurotrophins in activity-dependent neuronal plasticity. Microsc. Res. Tech. 45, 262–275 (1999).

    Article  CAS  Google Scholar 

  15. Hartmann, M., Heumann, R. & Lessmann, V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 20, 5887–5897 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Frerking, M., Malenka, R.C. & Nicoll, R.A. Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus. J. Neurophysiol. 80, 3383–3386 (1998).

    Article  CAS  Google Scholar 

  18. Tanaka, T., Saito, H. & Matsuki, N. Inhibition of GABAa synaptic responses by brain-derived neurotrophic factor (BDNF) in rat hippocampus. J. Neurosci. 17, 2959–2966 (1997).

    Article  CAS  Google Scholar 

  19. Kang, H., Jia, L., Suh, K., Tang, L. & Schuman, E. Determinants of BDNF-induced hippocampal synaptic plasticity: role of the TrkB receptor and the kinectics of neurotrophin delivery. Learn. Mem. 3, 188–196 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Sommerfeld, M.T., Schweigreiter, R., Barde, Y.A. & Hoppe, E. Down-regulation of the neurotrophin receptor TrkB following ligand binding. Evidence for an involvement of the proteasome and differential regulation of TrkA and TrkB. J. Biol. Chem. 275, 8982–8990 (2000).

    Article  CAS  Google Scholar 

  22. Haapasalo, A. et al. Regulation of TRKB surface expression by brain-derived neurotrophic factor and truncated TRKB isoforms. J. Biol. Chem. 277, 43160–43167 (2002).

    Article  CAS  Google Scholar 

  23. Carter, B.D., Zirrgiebel, U. & Barde, Y.A. Differential regulation of p21ras activation in neurons by nerve growth factor and brain-derived neurotrophic factor. J. Biol. Chem. 270, 21751–21757 (1995).

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Finkbeiner, S. et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron 19, 1031–1047 (1997).

    Article  CAS  Google Scholar 

  27. Ying, S.W. et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J. Neurosci. 22, 1532–1540 (2002).

    Article  CAS  Google Scholar 

  28. Sato, M., Suzuki, K. & Nakanishi, S. NMDA receptor stimulation and brain-derived neurotrophic factor upregulate homer 1a mRNA via the mitogen-activated protein kinase cascade in cultured cerebellar granule cells. J. Neurosci. 21, 3797–3805 (2001).

    Article  CAS  Google Scholar 

  29. Yin, Y., Edelman, G.M. & Vanderklish, P.W. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc. Natl. Acad. Sci. USA 99, 2368–2373 (2002).

    Article  CAS  Google Scholar 

  30. Shimada, A., Mason, C.A. & Morrison, M.E. TrkB signaling modulates spine density and morphology independent of dendrite structure in cultured neonatal Purkinje cells. J. Neurosci. 18, 8559–8570 (1998).

    Article  CAS  Google Scholar 

  31. McAllister, A.K., Lo, D.C. & Katz, L.C. Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15, 791–803 (1995).

    Article  CAS  Google Scholar 

  32. Tyler, W.J. & Pozzo-Miller, L. Miniature synaptic transmission and BDNF modulate dendritic spine growth and form in rat CA1 neurones. J. Physiol. 553, 497–509 (2003).

    Article  CAS  Google Scholar 

  33. Levine, E.S., Crozier, R.A., Black, I.B. & Plummer, M.R. Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity. Proc. Natl. Acad. Sci. USA 95, 10235–10239 (1998).

    Article  CAS  Google Scholar 

  34. Kao, S., Jaiswal, R.K., Kolch, W. & Landreth, G.E. Identification of the mechanisms regulating the differential activation of the MAPK cascade by epidermal growth factor and nerve growth factor in PC12 cells. J. Biol. Chem. 276, 18169–18177 (2001).

    Article  CAS  Google Scholar 

  35. Lessmann, V., Gottmann, K. & Heumann, R. BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurons. Neuroreport 6, 21–25 (1994).

    Article  CAS  Google Scholar 

  36. 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).

    Article  CAS  Google Scholar 

  37. Hering, H. & Sheng, M. Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis. J. Neurosci. 23, 11759–11769 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the National Cancer Institute, Center for Cancer Research Fellows Editorial Board and G. Nagappan for the thoughtful comments and suggestions. We thank W.H. Wilson for his innovative research in cancer therapy that helped us conceive this work. This work was supported by the Intramural Research Programs of the National Institute on Child Health and Human Development and the National Institute of Mental Health.

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Authors

Contributions

Y.J. conducted the biology and morphology experiments and wrote the manuscript. Y.L. prepared hippocampal slices and conducted the extracellular recording in slice. F.Y. conducted the whole-cell recording in slices. W.S. conducted the electrophysiology experiments. T.T.-T.T. prepared neuron culture and conducted morphology experiments. L.F. performed the immunostaining and biology experiments. S.D. supervised the project. B.L. supervised the project, designed the experiments and wrote the paper.

Corresponding author

Correspondence to Bai Lu.

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The authors declare no competing financial interests.

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Ji, Y., Lu, Y., Yang, F. et al. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 13, 302–309 (2010). https://doi.org/10.1038/nn.2505

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