Dynamic nanoscale architecture of synaptic vesicle fusion in mouse hippocampal neurons

Kroll, Jana; Kravčenko, Uljana; Sadeghi, Mohsen; Diebolder, Christoph A.; Ivanov, Lia; Lubas, Małgorzata; Sprink, Thiemo; Schacherl, Magdalena; Kudryashev, Mikhail; Rosenmund, Christian

Dynamic nanoscale architecture of synaptic vesicle fusion in mouse hippocampal neurons

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Item Type:	Article
Title:	Dynamic nanoscale architecture of synaptic vesicle fusion in mouse hippocampal neurons
Creators Name:	Kroll, Jana, Kravčenko, Uljana, Sadeghi, Mohsen, Diebolder, Christoph A., Ivanov, Lia, Lubas, Małgorzata, Sprink, Thiemo, Schacherl, Magdalena, Kudryashev, Mikhail and Rosenmund, Christian
Abstract:	Synaptic vesicle (SV) fusion is not only tightly coordinated but also happens at a millisecond timescale. Competing models for fusion initiation and propagation suggest tight docking and hemifusion of SVs or localized lipid rearrangements leading to tip-like membrane contacts. Yet, a direct nanoscale examination of the full SV fusion sequence has been lacking. Here, we establish a workflow for timed in situ cryo-electron tomography of optogenetically stimulated mouse neurons to capture the complete SV fusion sequence - from SV recruitment to fusion pore formation, opening and collapse - with near-native structural preservation. Notably, tethered SVs directly undergo fusion initiation via stalk formation, without preceding tight docking or SV flattening. The plasma membrane forms a minimal dimple during fusion initiation, contradicting preceding models that invoke strong membrane bending prior to fusion. In addition, we observe filaments linking fusing SVs to adjacent SVs, indicating a physical link between fusion and SV resupply.
Keywords:	Cell Membrane, Cryoelectron Microscopy, Hippocampus, Membrane Fusion, Neurons, Optogenetics, Synaptic Vesicles, Animals, Mice
Source:	Nature Communications
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Volume:	16
Number:	1
Page Range:	11131
Date:	15 December 2025
Official Publication:	https://doi.org/10.1038/s41467-025-67291-6
PubMed:	View item in PubMed
Related to:	URL URL Type https://doi.org/10.2210/pdb5w5d/pdb External Dataset https://doi.org/10.2210/pdb4jeu/pdb External Dataset https://doi.org/10.2210/pdb7udb/pdb External Dataset https://doi.org/10.2210/pdb7t7v/pdb External Dataset https://github.com/MohsenSadeghi/meso_synaptic_vesicle_fusion Software https://ftp.mi.fu-berlin.de/pub/msadeghi/synaptic_vesicle/ UNSPECIFIED

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