Dynamic nanoscale architecture of synaptic vesicle fusion in mouse hippocampal neurons

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

Nature Communications12/13/2025·DOI·Read paper

Abstract

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.

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