title: Munc13 controls the location and efficiency of dense-core vesicle release in neurons.
abstract: Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2-null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.
authors.affiliation: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, 1081 HV Amsterdam, Netherlands.
authors.forename: Rhea
authors.initials: R
authors.lastname: van de Bospoort
authors.forename: Margherita
authors.initials: M
authors.lastname: Farina
authors.forename: Sabine K
authors.initials: SK
authors.lastname: Schmitz
authors.forename: Arthur
authors.initials: A
authors.lastname: de Jong
authors.forename: Heidi
authors.initials: H
authors.lastname: de Wit
authors.forename: Matthijs
authors.initials: M
authors.lastname: Verhage
authors.forename: Ruud F
authors.initials: RF
authors.lastname: Toonen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C503321:Unc13a protein, mouse; C485549:Unc13b protein, mouse