"Kiss-shrink-run" unifies mechanisms for synaptic vesicle exocytosis and hyperfast recycling

Science. 2025 Oct 16;390(6770):eads7954. doi: 10.1126/science.ads7954. Epub 2025 Oct 16.

Abstract

Synaptic vesicle (SV) exocytosis underpins neuronal communication, yet its nanoscale dynamics remain poorly understood owing to limitations in visualizing rapid events in situ. Here, we used optogenetics-coupled, time-resolved cryo-electron tomography to capture SV exocytosis in rat hippocampal synapses. Within 4 milliseconds of synaptic activation, SVs transiently "kiss" the plasma membrane, forming a ~4-nanometer lipidic fusion pore flanked by putative soluble NSF-attachment protein receptor (SNARE) complexes and then rapidly "shrink" to approximately half of their original surface area. By 70 milliseconds, most shrunken SVs recycle via a "run-away" pathway, whereas others collapse into the presynaptic membrane. Ultrafast endocytosis retrieves the expanded presynaptic membrane after 100 milliseconds. These findings reveal a "kiss-shrink-run" mechanism of SV exocytosis and hyperfast recycling, reconciling conflicting models and elucidating the efficiency and fidelity of synaptic transmission.

MeSH terms

  • Animals
  • Cell Membrane / physiology
  • Cell Membrane / ultrastructure
  • Cryoelectron Microscopy
  • Electron Microscope Tomography
  • Endocytosis
  • Exocytosis*
  • Hippocampus / physiology
  • Optogenetics
  • Presynaptic Terminals / physiology
  • Presynaptic Terminals / ultrastructure
  • Rats
  • SNARE Proteins / metabolism
  • Synapses / physiology
  • Synapses / ultrastructure
  • Synaptic Transmission*
  • Synaptic Vesicles* / physiology
  • Synaptic Vesicles* / ultrastructure

Substances

  • SNARE Proteins