Cracking the Code of Neurotransmission
The brain’s ability to transmit signals rapidly hinges on the precise choreography of synaptic vesicle exocytosis. For decades, scientists debated whether vesicles simply “kiss” the presynaptic membrane and retreat (kiss-and-run) or fully collapse to release their neurotransmitters. A groundbreaking study from the University of Science and Technology of China (USTC), published in Science, introduces a third, time-resolved act: kiss-shrink-run. This new biophysical model reconciles two long-standing views and adds a shrinking phase that reshapes our understanding of synaptic efficiency and plasticity.
From Time-Resolved Imaging to a New Mechanism
At the heart of synaptic communication is the rapid exocytosis of neurotransmitters from synaptic vesicles (SVs) triggered by an action potential. To resolve how SV release unfolds on a millisecond timescale, the USTC team developed a time-resolved cellular cryo-electron tomography (cryo-ET) platform. By pairing optogenetic stimulation with ultra-fast plunge-freezing, they captured more than 1,000 tomograms of intact excitatory synapses at intervals from 0 to 300 milliseconds after a neural impulse.
Decoding the Timeline: Kiss-Shrink-Run
The high-speed snapshots reveal a three-act process. Within about 4 milliseconds, an SV forms a tiny fusion pore, a ‘kiss,’ roughly 4 nanometers in diameter. Rather than staying static, the vesicle then shrinks, reducing its exposed surface by about half. This “shrink” phase appears to be a critical intermediate step that primes vesicles for rapid recycling. By around 70 milliseconds, most SVs are reabsorbed or recycled via a fast “run” pathway. Some vesicles, however, undergo a classic full-collapse fusion into the presynaptic membrane. This hybrid sequence—kiss, shrink, then run—offers a cohesive explanation for how neurons maintain high-fidelity signaling with remarkable speed and reliability.
Implications for Neuroscience and Medicine
The kiss-shrink-run model resolves the apparent paradox between transient kiss-and-run events and irreversible full-collapse. It provides a unified framework for understanding how synapses can rapidly release neurotransmitters while keeping recycling rates high enough to sustain repeated signaling, which is essential for learning, memory, and behavior. Beyond basic science, this mechanism offers new angles for studying synaptic plasticity and neurodegenerative diseases where vesicle trafficking goes awry. By imaging the exact structural transitions at synapses, researchers can link molecular changes to functional outcomes, potentially guiding targeted therapies that preserve or restore efficient neurotransmission.
Cryo-ET as a New Standard in In Situ Neurobiology
Beyond the biological insight, the study demonstrates the power of cryo-ET as an in situ tool for observing membrane dynamics and protein–lipid interactions with unparalleled spatiotemporal resolution. The ability to freeze neuronal activity at precise moments preserves fleeting structural states that were previously inaccessible with conventional techniques. This methodological leap enables researchers to map the complete exocytosis–recycling timeline and to test how genetic or pharmacological perturbations alter each phase of the kiss-shrink-run sequence.
Conclusion: A Unified Picture of Synaptic Release
By capturing the kiss-shrink-run choreography, scientists now have a robust framework to understand how neurons achieve fast, reliable communication. The findings illuminate a previously hidden stage in the dance of neurotransmission and open doors to exploring how synaptic plasticity and brain disorders arise from subtle shifts in vesicle dynamics. As cryo-ET methodologies continue to evolve, the frontier of in situ neuroscience promises even deeper insights into the cellular mechanics that power thought and behavior.
