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

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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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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