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BDNF release from single cells elicits local dendritic growth in nearby neurons

Abstract

In cultured neurons, the exogenous application of neurotrophins (in homogenous concentrations) alters many features of axonal and dendritic arbors. In vivo, however, release of endogenous neurotrophins from neuronal processes creates spatially heterogeneous neurotrophin distributions. To probe the consequences of such endogenous neurotrophin distribution, we produced 'donor neurons' in ferret cortex brain slices that co-expressed brain-derived neurotrophic factor (BDNF) and red fluorescent protein (RFP). Using two-photon microscopy, we analyzed their effects on 'recipient neurons' that expressed green fluorescent protein (GFP) alone. BDNF released from dendrites and cell bodies acted directly on nearby recipient neurons to increase dendritic branching in a distance-dependent manner. Three-dimensional analysis of donor and recipient dendrites indicated that the BDNF source had to be within 4.5 μm to induce dendritic growth in the recipient neuron. Thus, BDNF released from an individual cell alters the structure of nearby dendrites on an exquisitely local scale.

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Figure 1: Local growth of dendrites of recipient neurons in areas near BDNF donor neurons.
Figure 2: BDNF-induced dendritic branching is highly restricted and correlates with distance from the source of BDNF.
Figure 3: Local dendritic growth is not a general result of neurotrophin overexpression.
Figure 4: Quantification of local dendritic lengths reveals distance-dependent, local effects of BDNF.
Figure 5: Overexpression of a dominant negative form of TrkB (T1) in recipient neurons blocks BDNF-induced branching.
Figure 6: BDNF donor neurons do not influence collateral branching of recipient neuron axons.
Figure 7: Spine and filopodia characteristics are not influenced by BDNF from donor neurons.

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References

  1. Bartlett, W.P. & Banker, G.A. An electron microscopic study of the development of axons and dendrites by hippocampal neurons in culture I. Cells which develop without intercellular contacts. J. Neurosci. 4, 1944–1953 (1984).

    Article  CAS  Google Scholar 

  2. Kossel, A., Lowel, S. & Bolz, J. Relationships between dendritic fields and functional architecture in striate cortex of normal and visually deprived cats. J. Neurosci. 15, 3913–3926 (1995).

    Article  CAS  Google Scholar 

  3. Katz, L.C. Local circuitry of identified projection neurons in cat visual cortex brain slices. J. Neurosci. 7, 1223–1249 (1987).

    Article  CAS  Google Scholar 

  4. Katz, L.C. & Constantine-Paton, M. Relationships between segregated afferents and postsynaptic neurons in the optic tectum of three-eyed frogs. J. Neurosci. 8, 3160–3180 (1988).

    Article  CAS  Google Scholar 

  5. Whitford, K.L. et al. Regulation of cortical dendrite development by Slit-Robo interactions. Neuron 33, 47–61 (2002).

    Article  CAS  Google Scholar 

  6. Nedivi, E., Wu, G.Y. & Cline, H.T. Promotion of dendritic growth by CPG15, an activity-induced signaling molecule. Science 281, 1863–1866 (1998).

    Article  CAS  Google Scholar 

  7. Kossel, A.H., Williams, C.V., Schweizer, M. & Kater, S.B. Afferent innervation influences the development of dendritic branches and spines via both activity-dependent and non-activity-dependent mechanisms. J. Neurosci. 17, 6314–6324 (1997).

    Article  CAS  Google Scholar 

  8. Zafra, F., Hengerer, B., Leibrock, J., Thoenen, H. & Lindholm, D. Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J. 9, 3545–3550 (1990).

    Article  CAS  Google Scholar 

  9. Ghosh, A., Carnahan, J. & Greenberg, M.E. Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618–1623 (1994).

    Article  CAS  Google Scholar 

  10. 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 

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

    Article  CAS  Google Scholar 

  12. 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 

  13. McAllister, A.K., Katz, L.C. & Lo, D.C. Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth. Neuron 18, 767–778 (1997).

    Article  CAS  Google Scholar 

  14. 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 

  15. Lom, B. & Cohen-Cory, S. Brain-derived neurotrophic factor differentially regulates retinal ganglion cell dendritic and axonal arborization in vivo. J. Neurosci. 19, 9928–9938 (1999).

    Article  CAS  Google Scholar 

  16. Horch, H.W., Kruttgen, A., Portbury, S.D. & Katz, L.C. Destabilization of cortical dendrites and spines by BDNF. Neuron 23, 353–364 (1999).

    Article  CAS  Google Scholar 

  17. Yacoubian, T.A. & Lo, D.C. Truncated and full-length trkB receptors regulate distinct modes of dendritic growth. Nat. Neurosci. 3, 342–349 (2000).

    Article  CAS  Google Scholar 

  18. Poo, M.-M. Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2, 1–9 (2001).

    Article  Google Scholar 

  19. Haapasalo, A. et al. Expression of the naturally occurring truncated trkB neurotrophin receptor induces outgrowth of filopodia and processes in neuroblastoma cells. Oncogene 18, 1285–1296 (1999).

    Article  CAS  Google Scholar 

  20. Klein, R., Conway, D., Parada, L.F. & Barbacid, M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61, 647–656 (1990).

    Article  CAS  Google Scholar 

  21. Middlemas, D.S., Lindberg, R.A. & Hunter, T. TrkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol. Cell Biol. 11, 143–153 (1991).

    Article  CAS  Google Scholar 

  22. Cohen-Cory, S. & Fraser, S.E. Effects of brain-derived neurotrophic factor on optic axon branching and remodeling in vivo. Nature 378, 192–196 (1995).

    Article  CAS  Google Scholar 

  23. Katz, L.C. Specificity in the development of vertical connections in cat striate cortex. Eur. J. Neurosci. 3, 1–9 (1991).

    Article  Google Scholar 

  24. Fischer, M., Kaech, S., Knutti, D. & Matus, A. Rapid actin-based plasticity in dendritic spines. Neuron 20, 847–854 (1998).

    Article  CAS  Google Scholar 

  25. Dunaevsky, A., Tashiro, A., Majewska, A., Mason, C. & Yuste, R. Developmental regulation of spine motility in mammalian central nervous system. Proc. Natl. Acad. Sci. USA 96, 13438–13443 (1999).

    Article  CAS  Google Scholar 

  26. Campenot, R.B. Development of sympathetic neurons in compartmentalized cultures. I. Local control of neurite growth by nerve growth factor. Dev. Biol. 93, 1–12 (1982).

    Article  CAS  Google Scholar 

  27. DiStefano, P.S. et al. The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons. Neuron 8, 983–993 (1992).

    Article  CAS  Google Scholar 

  28. Hendry, I., Stoeckel, K., Thoenen, H. & Iversen, L. The retrograde axonal transport of nerve growth factor. Brain Res. 68, 103–121 (1974).

    Article  CAS  Google Scholar 

  29. Kuruvilla, R., Ye, H.H. & Ginty, D.D. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 27, 499–512 (2000).

    Article  CAS  Google Scholar 

  30. Jarvis, C.R. et al. Neurotrophin modulation of NMDA receptors in cultured murine and isolated rat neurons. J. Neurophysiol. 78, 2363–2371 (1997).

    Article  CAS  Google Scholar 

  31. Kafitz, K.W., Rose, C.R., Thoenen, H. & Konnerth, A. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 401, 918–921 (1999).

    Article  CAS  Google Scholar 

  32. Ozdinler, P.H. & Erzurumlu, R.S. Regulation of neurotrophin-induced axonal responses via rho GTPases. J. Comp. Neurol. 438, 377–387 (2001).

    Article  CAS  Google Scholar 

  33. Tongiorgi, E., Righi, M. & Cattaneo, A. Activity-dependent dendritic targeting of BDNF and TrkB mRNAs in hippocampal neurons. J. Neurosci. 17, 9492–9505 (1997).

    Article  CAS  Google Scholar 

  34. Aoki, C. et al. Localization of brain-derived neurotrophic factor and TrkB receptors to postsynaptic densities of adult rat cerebral cortex. J. Neurosci. Res. 59, 454–463 (2000).

    Article  CAS  Google Scholar 

  35. Shepherd, G. & Greer, C. in The Synaptic Organization of the Brain (ed. Shepherd, G.) (Oxford Univ. Press, New York, 1998).

    Google Scholar 

  36. McAllister, A.K., Katz, L.C. & Lo, D.C. Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17, 1057–1064 (1996).

    Article  CAS  Google Scholar 

  37. Peichl, L. & Wassle, H. Size, scatter and coverage of ganglion-cell receptive-field centers in the cat retina. J. Physiol. 291, 117–141 (1979).

    Article  CAS  Google Scholar 

  38. Barde, Y.A., Edgar, D. & Thoenen, H. Purification of a new neurotrophic factor from the mammalian brain. EMBO 1, 549–553 (1982).

    Article  CAS  Google Scholar 

  39. Allendoerfer, K.L. et al. Regulation of neurotrophin receptors during the maturation of the mammalian visual system. J. Neurosci. 14, 1795–1811 (1994).

    Article  CAS  Google Scholar 

  40. Fryer, R.H. et al. Developmental and mature expression of full-length and truncated TrkB receptors in the rat forebrain. J. Comp. Neurol. 374, 21–40 (1996).

    Article  CAS  Google Scholar 

  41. Biffo, S., Offenhauser, N., Carter, B.D. & Barde, Y.A. Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development. Development 121, 2461–2470 (1995).

    CAS  PubMed  Google Scholar 

  42. Gallo, G. & Letourneau, P.C. Neurotrophins and the dynamic regulation of the neuronal cytoskeleton. J. Neurobiol. 44, 159–173 (2000).

    Article  CAS  Google Scholar 

  43. Murphy, D.D., Cole, N.B. & Segal, M. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons. Proc. Natl. Acad. Sci. USA 95, 11412–11417 (1998).

    Article  CAS  Google Scholar 

  44. Rutherford, L.C., Nelson, S.B. & Turrigiano, G.G. BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses. Neuron 21, 521–530 (1998).

    Article  CAS  Google Scholar 

  45. 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  Google Scholar 

  46. Dalva, M.B. & Katz, L.C. Rearrangements of synaptic connections in visual cortex revealed by laser photostimulation. Science 265, 255–258 (1994).

    Article  CAS  Google Scholar 

  47. Kryl, D. et al. Subcellular localization of full-length and truncated trk receptor isoforms in polarized neurons and epithelial cells. J. Neurosci. 19, 5823–5833 (1999).

    Article  CAS  Google Scholar 

  48. 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).

    Article  CAS  Google Scholar 

  49. Yuste, R. & Bonhoeffer, T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071–1089 (2001).

    Article  CAS  Google Scholar 

  50. Zervas, M. & Walkley, S.U. Ferret pyramidal cell dendritogenesis: changes in morphology and ganglioside expression during cortical development. J. Comp. Neurol. 413, 429–448 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Irving for technical assistance and D. Lo for incisive, helpful discussions. L.C.K. is an investigator in the Howard Hughes Medical Institute. This work was supported by National Institutes of Health grant EY-11553 and the Human Frontiers Science Program.

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Correspondence to Hadley Wilson Horch.

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Horch, H., Katz, L. BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat Neurosci 5, 1177–1184 (2002). https://doi.org/10.1038/nn927

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