Breaking the old dichotomy in neurotransmission
For decades, neuroscientists debated whether synaptic vesicles released neurotransmitters through a fleeting “kiss-and-run” event or an irreversible “full collapse” into the presynaptic membrane. A pioneering study from the University of Science and Technology of China (USTC) now reveals a nuanced third act—one that reconciles two long-standing models by showing a brief kiss, a rapid shrink, and a swift run of vesicles during neurotransmission.
Introducing the kiss-shrink-run model
The new model, described in a Science publication titled “Kiss-shrink-run unifies mechanisms for synaptic vesicle exocytosis and hyperfast recycling,” posits that synaptic vesicle (SV) exocytosis is not strictly transient nor entirely irreversible. Instead, SVs undergo a dynamic sequence: an initial ultrafast fusion pore forms (the kiss), the vesicle then shrinks, reducing its surface area, and finally either rapidly recycles or proceeds to full-collapse in select cases. This refined picture helps explain how neurons achieve both speed and reliability during neurotransmission.
How the study captured the moment in time
To visualize such rapid events, the research team developed a time-resolved, cellular cryo-electron tomography (cryo-ET) platform. They combined optogenetic stimulation—triggering neural activity with light—with high-speed plunge-freezing to preserve fleeting states in near-native conditions. By capturing more than 1,000 tomograms of intact excitatory synapses at time points ranging from 0 to 300 milliseconds after an action potential, the researchers were able to reconstruct the entire sequence of SV release and early recycling.
The millisecond timeline: from kiss to shrink to run
The imaging revealed a striking, quantifiable timeline. Within approximately 4 milliseconds after stimulation, vesicles formed a nascent fusion pore about 4 nanometers in diameter—the “kiss.” This pore then underwent a rapid structural reorganization, shrinking to roughly half of the vesicle’s original surface area and signaling a transition phase—the “shrink.” By about 70 milliseconds post-action potential, most vesicles were recycled through the “run” pathway, ready for another round of signaling. Yet, some vesicles underwent full-collapse fusion with the presynaptic membrane, indicating that the biological system retains a spectrum of release outcomes rather than a single fixed mechanism.
Why the kiss-shrink-run matters for brain function
This hybrid mechanism offers a robust framework for understanding how synapses maintain high-speed communication while preserving vesicles for rapid reuse. The rapid shrink and subsequent recycling align well with the brain’s need for precise timing in neural circuits underlying perception, learning, and memory. Moreover, the findings provide a structural basis for synaptic plasticity, a fundamental process implicated in cognitive flexibility and various neuropsychiatric conditions.
Implications for health and disease
By illuminating how SVs can rapidly release neurotransmitters and then quickly recycle, the kiss-shrink-run model could influence therapeutic strategies targeting synaptic dysfunction. Diseases characterized by impaired neurotransmission—such as certain neurodegenerative disorders and epilepsy—might be better understood through this integrated lens of fast exocytosis and efficient vesicle reuse. Researchers can now probe how alterations in the kiss, shrink, or run phases contribute to pathology, with the potential to identify novel drug targets for modulating synaptic efficacy.
A new standard for in situ neurobiology
Beyond the specific mechanism, the cryo-ET technique itself establishes a high bar for in situ analysis of membrane dynamics and molecular interactions. The approach preserves native cellular architecture while achieving unmatched spatiotemporal resolution, enabling scientists to study rapid biological processes in their natural context. As researchers apply this platform to other synaptic types and brain regions, the kiss-shrink-run framework may serve as a universal template for deciphering fast neuronal signaling across the nervous system.
