Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles (original) (raw)

Nature volume 400, pages 457–461 (1999)Cite this article

Abstract

Neurotransmitter release at synapses between nerve cells is mediated by calcium-triggered exocytotic fusion of synaptic vesicles1. Before fusion, vesicles dock at the presynaptic release site where they mature to a fusion-competent state1,2. Here we identify Munc13-1, a brain-specific presynaptic phorbol ester receptor3,4, as an essential protein for synaptic vesicle maturation. We show that glutamatergic hippocampal neurons from mice lacking Munc13-1 form ultrastructurally normal synapses whose synaptic-vesicle cycle is arrested at the maturation step. Transmitter release from mutant synapses cannot be triggered by action potentials, calcium-ionophores or hypertonic sucrose solution. In contrast, release evoked by α-latrotoxin is indistinguishable from wild-type controls, indicating that the toxin can bypass Munc13-1-mediated vesicle maturation. A small subpopulation of synapses of any given glutamatergic neuron as well as all synapses of GABA (γ-aminobutyric acid)-containing neurons are unaffected by Munc13-1 loss, demonstrating the existence of multiple and transmitter-specific synaptic vesicle maturation processes in synapses.

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References

  1. Südhof, T. C. The synaptic vesicle cycle: a cascade of protein–protein interactions. Nature 375, 645–653 (1995).
    Article ADS Google Scholar
  2. Zucker, R. S. Exocytosis: a molecular and physiological perspective. Neuron 17, 1049–1055 (1996).
    Article CAS Google Scholar
  3. Brose, N., Hofmann, K., Hata, Y. & Südhof, T. C. Mammalian homologues of C. elegans unc-13 gene define novel family of C2-domain proteins. J. Biol. Chem. 270, 25273–25280 (1995).
    Article CAS Google Scholar
  4. Betz, A.et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron 21, 123–136 (1998).
    Article CAS Google Scholar
  5. Stevens, C. F. & Tsujimoto, T. Estimates for the pool size of releasable quanta at a single central synapse and for the time required to fill a pool. Proc. Natl Acad. Sci. USA 92, 846–894 (1995).
    Article ADS CAS Google Scholar
  6. Rosenmund, C. & Stevens, C. F. Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron 16, 1197–1207 (1996).
    Article CAS Google Scholar
  7. Zucker, R. S. Changes in the statistics of transmitter release during facilitation. J. Physiol. 229, 787–810 (1973).
    Article CAS Google Scholar
  8. Zucker, R. S. Short-term synaptic plasticity. Annu. Rev. Neurosci. 12, 13–31 (1989).
    Article CAS Google Scholar
  9. Rosenmund, C., Clements, J. D. & Westbrook, G. L. Nonuniform probability of glutamate release at a hippocampal synapse. Science 262, 754–757 (1993).
    Article ADS CAS Google Scholar
  10. Hessler, N. A., Shirke, A. M. & Malinow, R. The probability of transmitter release at a mammalian synapse. Nature 366, 569–572 (1993).
    Article ADS CAS Google Scholar
  11. Rosenmund, C., Feltz, A. & Westbrook, G. L. Synaptic NMDA receptor channels have a low open probability. J. Neurosci. 15, 2788–2795 (1995).
    Article CAS Google Scholar
  12. Geppert, M.et al. Synaptotagmin I: a major Ca2+-sensor for transmitter release at a central synapse. Cell 79, 717–727 (1994).
    Article CAS Google Scholar
  13. Krasnoperov, V. G.et al. α-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron 18, 925–937 (1997).
    Article CAS Google Scholar
  14. Lelianova, V. G.et al. α-Latrotoxin receptor, latrophilin, is a novel member of the secretin family of G-protein coupled receptors. J. Biol. Chem. 272, 21504–21508 (1997).
    Article CAS Google Scholar
  15. Martin, T. F. Mechanisms of protein secretion in endocrine and exocrine cells. Vitamins Hormones 54, 207–226 (1998).
    Article CAS Google Scholar
  16. Bekkers, J. M. & Stevens, C. F. Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in culture. Proc. Natl Acad. Sci. USA 88, 7834–7838 (1991).
    Article ADS CAS Google Scholar
  17. Boyer, C., Schikorski, T. & Stevens, C. F. Comparison of hippocampal dendritic spines in culture and in brain. J. Neurosci. 18, 5294–5300 (1998).
    Article CAS Google Scholar

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Acknowledgements

We thank J. Rettig and U. Ashery for stimulating discussions; S. Röglin, A. Kanbach and C. Casper for help with animal colonies; J. Ficner and R. Schubert for artwork; I. Herfort, S. Schmidt and S. Wenger for technical assistance; and F. Benseler and I. Thanhäuser for DNA synthesis and sequencing. This work was supported by grants from the German Research Foundation and the Max-Planck-Society. C.R. and N.B. are Heisenberg Fellows of the German Research Foundation.

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Authors and Affiliations

  1. Max-Planck-Institut für Experimentelle Medizin, AG Molekulare Neurobiologie, Hermann-Rein-Str. 3, Göttingen, D-37075, Bundesrepublik, Deutschland
    Iris Augustin & Nils Brose
  2. Abteilung Membranbiophysik, Max-Planck-Institut fr Biophysikalische Chemie, Am Fassberg 11, Göttingen, D-37077, Bundesrepublik, Deutschland
    Christian Rosenmund
  3. Department of Molecular Genetics, Center for Basic Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, 75235, Texas, USA
    Thomas C. Südhof

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  1. Iris Augustin
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  2. Christian Rosenmund
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  3. Thomas C. Südhof
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  4. Nils Brose
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Correspondence toNils Brose.

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Augustin, I., Rosenmund, C., Südhof, T. et al. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles.Nature 400, 457–461 (1999). https://doi.org/10.1038/22768

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