title: Vesicular Synaptobrevin/VAMP2 Levels Guarded by AP180 Control Efficient Neurotransmission.
abstract: Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180(-/-)/Syb2(+/-) mice results in perinatal lethality, whereas Syb2(+/-) mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient neurotransmission and SV reformation.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
authors.forename: Seong Joo
authors.initials: SJ
authors.lastname: Koo
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
authors.forename: Gaga
authors.initials: G
authors.lastname: Kochlamazashvili
authors.affiliation: NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rost
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Puchkov
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
authors.forename: Niclas
authors.initials: N
authors.lastname: Gimber
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany.
authors.forename: Georgi
authors.initials: G
authors.lastname: Tadeus
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schmoranzer
authors.affiliation: NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenmund
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry and Pharmacy, 14195 Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany. Electronic address: haucke@fmp-berlin.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie, Robert-Roessle-Straße 10, 13125 Berlin, Germany. Electronic address: maritzen@fmp-berlin.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Maritzen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D034041:Monomeric Clathrin Assembly Proteins / Q000737:chemistry / Q000378:metabolism*; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism / Q000648:ultrastructure; D050988:Vesicle-Associated Membrane Protein 2 / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*
chemical_list: D034041:Monomeric Clathrin Assembly Proteins; D050988:Vesicle-Associated Membrane Protein 2; C439023:clathrin assembly protein AP180; C494808:vesicle-associated membrane protein 2, mouse