Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles.
Neurotransmitter release at synapses between nerve cells is mediated by calcium-triggered exocytotic fusion of synaptic vesicles. Before fusion, vesicles dock at the presynaptic release site where they mature to a fusion-competent state. Here we identify Munc13-1, a brain-specific presynaptic phorbol ester receptor, 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 alpha-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 (gamma-aminobutyric acid)-containing neurons are unaffected by Munc13-1 loss, demonstrating the existence of multiple and transmitter-specific synaptic vesicle maturation processes in synapses.
Augustin
I
I
Max-Planck-Institut für Experimentelle Medizin, AG Molekulare Neurobiologie, Göttingen, Bundesrepublik Deutschland.
Rosenmund
C
C
Südhof
T C
TC
Brose
N
N
D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008561:Membrane Fusion / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D017384:Sequence Deletion; D013111:Spider Venoms / Q000494:pharmacology; D013569:Synapses / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology* / Q000648:ultrastructure; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D013111:Spider Venoms; C485549:Unc13b protein, mouse; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C020763:alpha-latrotoxin; D016291:Dizocilpine Maleate