“Kiss-shrink-run” unifies mechanisms for synaptic vesicle exocytosis and hyperfast recycling
- Chang-Lu Tao
- Chong-Li Tian
- Yun-Tao Liu
- Zhen-Hang Lu
- Lei Qi
- Xiao-Wei Li
- Chao Li
- Xuefeng Shen
- Min-Ling Gu
- Wen-Lan Huang
- Shuo Liu
- Lei-Qing Yang
- Zhenghan Liao
- Xiaomin Ma
- Jing Wu
- Jianyuan Sun
- Peiyi Wang
- Pak-Ming Lau
- Z. Hong Zhou
- Guo-Qiang Bi
2025-10-17
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.