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Vesicular synaptobrevin/VAMP2 levels guarded by AP180 control efficient neurotransmission

Item Type:Article
Title:Vesicular synaptobrevin/VAMP2 levels guarded by AP180 control efficient neurotransmission
Creators Name:Koo, S.J. and Kochlamazashvili, G. and Rost, B. and Puchkov, D. and Gimber, N. and Lehmann, M. and Tadeus, G. and Schmoranzer, J. and Rosenmund, C. and Haucke, V. and Maritzen, T.
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.
Keywords:Cultured Cells, Endocytosis, Excitatory Postsynaptic Potentials, Exocytosis, HEK293 Cells, Hippocampus, Inbred C57BL Mice, Knockout Mice, Monomeric Clathrin Assembly Proteins, Organ Culture Techniques, Protein Transport, Synaptic Transmission, Synaptic Vesicles, Transgenic Mice, Vesicle-Associated Membrane Protein 2, 129 Strain Mice, Animals, Mice
Publisher:Cell Press
Page Range:330-344
Date:21 October 2015
Official Publication:https://doi.org/10.1016/j.neuron.2015.08.034
PubMed:View item in PubMed

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