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Synapsins as mediators of BDNF-enhanced neurotransmitter release

Nature Neuroscience volume 3, pages 323–329 (2000)Cite this article

Abstract

We examined enhancement of synaptic transmission by neurotrophins at the presynaptic level. In a synaptosomal preparation, brain-derived neurotrophic factor (BDNF) increased mitogen-activated protein (MAP) kinase-dependent synapsin I phosphorylation and acutely facilitated evoked glutamate release. PD98059, used to inhibit MAP kinase activity, markedly decreased synapsin I phosphorylation and concomitantly reduced neurotransmitter release. The stimulation of glutamate release by BDNF was strongly attenuated in mice lacking synapsin I and/or synapsin II. These results indicate a causal link of synapsin phosphorylation via BDNF, TrkB receptors and MAP kinase with downstream facilitation of neurotransmitter release.

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Figure 1: BDNF stimulates evoked release of glutamate from rat brain synaptosomes.
Figure 2: BDNF stimulates TrkB receptor tyrosine phosphorylation, p44erk1 and p42erk2 MAP kinase activity and phosphorylation of synapsin I at MAP kinase-dependent sites in synaptosomes.
Figure 3: Effects of PD98059, a specific inhibitor of MAP kinase kinase activity, on p44erk1 and p42erk2 MAP kinase activity and on the phosphorylation state of synapsin I at MAP kinase-dependent sites.
Figure 4: In small synaptic vesicles in the nerve terminal, synapsin is the predominant protein phosphorylated by exogenous MAP kinase (p44mpk).
Figure 5: BDNF facilitation of evoked glutamate release is attenuated in synaptosomes from synapsin-deficient mice.

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References

  1. Lewin, G. R. & Barde, Y. A. Physiology of the neurotrophins. Annu. Rev. Neurosci. 19, 289–317 (1996).

    Article  CAS  Google Scholar 

  2. Thoenen, H. Neurotrophins and neuronal plasticity. Science 270, 593–598 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. 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 

  7. Stoop, R. & Poo, M. M. Synaptic modulation by neurotrophic factors: differential and synergistic effects of brain-derived neurotrophic factor and ciliary neurotrophic factor. J. Neurosci. 16, 3256–3264 (1996).

    Article  CAS  Google Scholar 

  8. Li, Y. X. et al. Expression of a dominant negative TrkB receptor, T1, reveals a requirement for presynaptic signaling in BDNF-induced synaptic potentiation in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA 95, 10884–10889 (1998).

    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. Figurov, A., Pozzo, M. 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 

  11. Carmignoto, G., Pizzorusso, T., Tia, S. & Vicini, S. Brain-derived neurotrophic factor and nerve growth factor potentiate excitatory synaptic transmission in the rat visual cortex. J. Physiol. (Lond.) 498, 153–164 (1997).

    Article  CAS  Google Scholar 

  12. Gottschalk, W., Pozzo, M. 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).

    Article  CAS  Google Scholar 

  13. Messaoudi, E., Bardsen, K., Srebro, B. & Bramham, C. R. Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentate gyrus. J. Neurophysiol. 79, 496–499 (1998).

    Article  CAS  Google Scholar 

  14. Sudhof, T. C. et al. Synapsins: mosaics of shared and individual domains in a family of synaptic vesicle phosphoproteins. Science 245, 1474–1480 (1989).

    Article  CAS  Google Scholar 

  15. Kao, H. T. et al. A third member of the synapsin gene family. Proc. Natl. Acad. Sci. USA 95, 4667–4672 (1998).

    Article  CAS  Google Scholar 

  16. Hosaka, M. & Sudhof, T. C. Synapsin III, a novel synapsin with an unusual regulation by Ca2+. J. Biol. Chem. 273, 13371–13374 (1998).

    Article  CAS  Google Scholar 

  17. Greengard, P., Valtorta, F., Czernik, A. J. & Benfenati, F. Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 259, 780–785 (1993).

    Article  CAS  Google Scholar 

  18. Llinas, R., Gruner, J. A., Sugimori, M., McGuinness, T. L. & Greengard, P. Regulation by synapsin I and Ca2+-calmodulin-dependent protein kinase II of the transmitter release in squid giant synapse. J. Physiol. (Lond.) 436, 257–282 (1991).

    Article  CAS  Google Scholar 

  19. Pieribone, V. A. et al. Distinct pools of synaptic vesicles in neurotransmitter release. Nature 375, 493–497 (1995).

    Article  CAS  Google Scholar 

  20. Li, L. et al. Impairment of synaptic vesicle clustering and of synaptic transmission, and increased seizure propensity, in synapsin I-deficient mice. Proc. Natl. Acad. Sci. USA 92, 9235–9239 (1995).

    Article  CAS  Google Scholar 

  21. Hilfiker, S. et al. Two sites of action for synapsin domain E in regulating neurotransmitter release. Nat. Neurosci. 1, 29–35 (1998).

    Article  CAS  Google Scholar 

  22. Jovanovic, J. N. et al. Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions. Proc. Natl. Acad. Sci. USA 93, 3679–3683 (1996).

    Article  CAS  Google Scholar 

  23. Matsubara, M. et al. Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions. J. Biol. Chem. 271, 21108–21113 (1996).

    Article  CAS  Google Scholar 

  24. Segal, R. A. & Greenberg, M. E. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 19, 463–489 (1996).

    Article  CAS  Google Scholar 

  25. McMahon, H. T. & Nicholls, D. G. The bioenergetics of neurotransmitter release Biochim. Biophys. Acta 1059, 243–264 (1991).

    Article  CAS  Google Scholar 

  26. Sihra, T. S. in Posttranslational Modifications: Techniques and Protocols (ed. Hemmings, H. C. Jr.) 67–119 (Humana Press, Totowa, New Jersey, 1997).

    Google Scholar 

  27. Perkinton, M. S. & Sihra, T. S. Presynaptic GABA(B) receptor modulation of glutamate exocytosis from rat cerebrocortical nerve terminals: receptor decoupling by protein kinase C. J. Neurochem. 70, 1513–1522 (1998).

    Article  CAS  Google Scholar 

  28. Sanchez, P. J., Budd, D. C., Herrero, I., Vazquez, E. & Nicholls, D. G. Presynaptic receptors and the control of glutamate exocytosis. Trends Neurosci. 19, 235–239 (1996).

    Article  Google Scholar 

  29. Sihra, T. S., Bogonez, E. & Nicholls, D. G. Localized Ca2+ entry preferentially effects protein dephosphorylation, phosphorylation, and glutamate release. J. Biol. Chem. 267, 1983–1989 (1992).

    CAS  PubMed  Google Scholar 

  30. Nicholls, D. G. & Sihra, T. S. Synaptosomes possess an exocytotic pool of glutamate. Nature 321, 772–773 (1986).

    Article  CAS  Google Scholar 

  31. Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase in vitro and in vivo. J. Biol. Chem. 270, 27489–27494 (1995).

    Article  CAS  Google Scholar 

  32. Huttner, W. B., Schiebler, W., Greengard, P. & De Camilli, P. Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation. J. Cell Biol. 96, 1374–1388 (1983).

    Article  CAS  Google Scholar 

  33. Lu, B., Yokoyama, M., Dreyfus, C. F. & Black, I. B. Depolarizing stimuli regulate nerve growth factor gene expression in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA 88, 6289–6292 (1991).

    Article  CAS  Google Scholar 

  34. Wetmore, C., Olson, L. & Bean, A. J. Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors. J. Neurosci. 14, 1688–1700 (1994).

    Article  CAS  Google Scholar 

  35. Fawcett, J. P. et al. Detection of brain-derived neurotrophic factor in a vesicular fraction of brain synaptosomes. J. Biol. Chem. 272, 8837–8840 (1997).

    Article  CAS  Google Scholar 

  36. Kim, H. G., Wang, T., Olafsson, P. & Lu, B. Neurotrophin 3 potentiates neuronal activity and inhibits gamma-aminobutyratergic synaptic transmission in cortical neurons. Proc. Natl. Acad. Sci. USA 91, 12341–12345 (1994).

    Article  CAS  Google Scholar 

  37. Boulanger, L. & Poo, M.-M. Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation. Nat. Neurosci. 2, 346–351 (1999).

    Article  CAS  Google Scholar 

  38. Kang, H., Welcher, A. A., Shelton, D. & Schuman, E. M. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653–664 (1997).

    Article  CAS  Google Scholar 

  39. Toledo, A. 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).

    Article  Google Scholar 

  40. 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 

  41. Nikodijevic, B. & Guroff, G. Nerve growth factor-stimulated calcium uptake into PC12 cells: uniqueness of the channel and evidence for phosphorylation. J. Neurosci. Res. 31, 591–599 (1992).

    Article  CAS  Google Scholar 

  42. Levine, E. S., Dreyfus, C. F., Black, I. B. & Plummer, M. R. Differential effects of NGF and BDNF on voltage-gated calcium currents in embryonic basal forebrain neurons. J. Neurosci. 15, 3084–3091 (1995).

    Article  CAS  Google Scholar 

  43. Li, Y. X., Zhang, Y., Lester, H. A., Schuman, E. M. & Davidson, N. Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. J. Neurosci. 18, 10231–10240 (1998).

    Article  CAS  Google Scholar 

  44. Barrie, A., Chieregatti, E., Miloso, M., Benfenati, F. & Valtorta, F. Epidermal growth factor-mediated inhibition of neurotransmitter glutamate release from rat forebrain synaptosomes. Mol. Pharmacol. 49, 399–403 (1996).

    CAS  PubMed  Google Scholar 

  45. Nicholls, D. G., Sihra, T. S. & Sanchez-Prieto, J. The role of the plasma membrane and intracellular organelles in synaptosomal calcium regulation. Soc. Gen. Physiol. Ser. 42, 31–43 (1987).

    CAS  PubMed  Google Scholar 

  46. Otto, H., Hanson, P. I. & Jahn, R. Assembly and disassembly of a ternary complex of synaptobrevin, syntaxin, and SNAP-25 in the membrane of synaptic vesicles. Proc. Natl. Acad. Sci. USA 94, 6197–6201 (1997).

    Article  CAS  Google Scholar 

  47. Ryan, T. A., Li, L., Chin, L. S., Greengard, P. & Smith, S. J. Synaptic vesicle recycling in synapsin I knock-out mice. J. Cell Biol. 134, 1219–1227 (1996).

    Article  CAS  Google Scholar 

  48. Ferreira, A. et al. Distinct roles of synapsin I and synapsin II during neuronal development. Mol. Med. 4, 22–28 (1998).

    Article  CAS  Google Scholar 

  49. Perkinton, M. S. & Sihra, T. S. A high affinity presynaptic kainate-type glutamate receptor facilitates glutamate exocytosis from cerebral cortex nerve terminals (synaptosomes). Neuroscience 90, 1279–1290 (1999).

    Article  Google Scholar 

  50. Sanghera, J. S., Paddon, H. B., Bader, S. A. & Pelech, S. L. Purification and characterization of a maturation-activated myelin basic protein kinase from sea star oocytes. J. Biol. Chem. 265, 52–57 (1990).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Regeneron Pharmaceuticals for supplying BDNF and NT-3 and A. R. Saltiel (Parke-Davis Pharmaceutical Research Division of Warner-Lambert) for providing us with PD98059. This work was supported by grants from the National Institute of Mental Health and National Institute on Aging (USPHS MH39327 and AG15072) to P.G. and a University Award and grants from the Wellcome Trust (UK) to T.S.S.

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Author notes

  1. Jasmina N. Jovanovic

    Present address: Department of Pharmacology University College London, London, WC1E 6BT, UK

Authors and Affiliations

  1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, 10021, New York, USA

    Jasmina N. Jovanovic, Andrew J. Czernik, Allen A. Fienberg & Paul Greengard

  2. Department of Pharmacology University College London, London, WC1E 6BT, UK

    Talvinder S. Sihra

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Correspondence to Talvinder S. Sihra.

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Jovanovic, J., Czernik, A., Fienberg, A. et al. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 3, 323–329 (2000). https://doi.org/10.1038/73888

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