USTC scientists uncover mystery of neurotransmission with time-resolved cryo-ET

A research team led by Prof. BI Guo-Qiang from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS), in collaboration with several domestic and international institutions, has resolved a 50-year-old controversy in neuroscience. By employing a self-developed, time-resolved cryo-electron tomography (cryo-ET) technique, the team has delineated the intricate choreography of synaptic vesicle (SV) release and rapid recycling, the cornerstone of neural communication. Their findings, which introduce a new biophysical mechanism termed the “Kiss-Shrink-Run”, were published in Science on October 17 (Beijing time).

Our brain function relies on efficient and precise synaptic transmission between neurons. When an electrical signal, known as action potential, reaches a neuron’s terminal, SV release neurotransmitters to relay the information across the synapse. However, due to technical limitations, the biophysical mechanisms governing this process have remained only partially understood, with a long-standing debate over the existence of transient “kiss-and-run” fusion versus irreversible “full-collapse” fusion in central synapses.

To address this challenge, the team developed a time-resolved, cellular cryo–electron tomography (cryo-ET) method by integrating optogenetic stimulation (light-controlled neural activation) with high-speed plunge-freezing to capture snapshots of cultured neuronal synapses. Using this technique, they acquired over 1,000 tomograms of intact excitatory synapses, frozen at time points ranging from 0 to 300 milliseconds post-action potential. Through detailed structural and statistical analyses, the team reconstructed the complete timeline of vesicle exocytosis and rapid recycling: Within 4 milliseconds after action potential, the vesicle first fuses with the presynaptic membrane to form a ~4 nanometer fusion pore (“kiss”), then shrinks into a small vesicle with half its original surface area (“shrink”). By 70 milliseconds, most of these small vesicles begin to be recycled via the “run” pathway, while the remaining ones undergo “full-collapse” fusion with the presynaptic membrane.

This work overturns the classic dichotomy: SV release is neither pure kiss-and-run nor full-collapse, but includes a key shrinking phase. The “kiss-shrink-run” mechanism unifies the long-debated models and provides a structural basis for the efficiency and fidelity of synaptic transmission. It also offers a fresh perspective on neurotransmission, synaptic plasticity, and related brain functions and diseases. In parallel, the technology establishes an in situ framework to interrogate membrane dynamics and molecular interactions with high spatiotemporal precision.