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Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles

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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Figure 1: Glutamatergic but not GABA-mediated neurons show strongly impaired synaptic transmission in Munc13-1-deficient mice.
Figure 2: Impaired glutamatergic neurotransmission results from a decreased readily releasable vesicle pool.
Figure 3: Selective silencing of most glutamatergic synapses in Munc13-1-deficient neurons and effect of α-latrotoxin.
Figure 4: Munc13-1-deficient neurons form ultrastructurally normal synapses.

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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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  4. Nils Brose
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Correspondence to Nils 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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