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Researchers have identified a new three-step process for neurotransmitter release that resolves a central, decades-long debate in neuroscience. A team from the University of Science and Technology of China (USTC) used cutting-edge imaging technology to directly observe how brain cells communicate at the most fundamental level, revealing a sequence they have named the “kiss-shrink-run” mechanism. This discovery unifies two previously competing theories and provides a far more detailed and nuanced picture of the synaptic activity that underpins all brain function.
The findings are significant because the process of releasing neurotransmitters from tiny sacs, or synaptic vesicles, is the basis of all neuronal communication, affecting everything from muscle movement to memory formation. For over 50 years, scientists have argued whether these vesicles fully merge with a neuron’s membrane to release their chemical cargo in a “full-collapse” model or briefly connect and detach in a “kiss-and-run” process. By providing a definitive answer that integrates both ideas, this new framework deepens our understanding of synaptic plasticity—the cellular basis for learning—and may open new avenues for investigating neurological disorders linked to faulty synaptic mechanics.
A Long-Standing Neurological Puzzle
The debate over how synaptic vesicles release their neurotransmitters has been a persistent puzzle in cellular neuroscience. Two primary models have dominated the field. The first, known as full-collapse fusion, proposed that a vesicle completely merges with the presynaptic membrane, the outer wall of the neuron. This irreversible fusion would flatten the vesicle structure into the membrane, dumping its entire payload of neurotransmitters into the synapse, the gap between neurons. The vesicle’s components would then need to be gathered and reassembled through a slower, energy-intensive process called clathrin-mediated endocytosis.
In contrast, the “kiss-and-run” hypothesis suggested a more efficient, transient interaction. In this model, a vesicle would temporarily dock at the membrane and form a tiny, fleeting fusion pore—just large enough to release its neurotransmitters. After this brief “kiss,” the vesicle would detach, or “run,” largely intact and ready for rapid refilling and reuse. This mechanism would be faster and conserve more resources. While evidence existed for both models under different experimental conditions, scientists could never definitively prove which one was the dominant method used in typical brain synapses, leading to a decades-long stalemate.
Visualizing Communication in Milliseconds
The breakthrough by the USTC team, led by Professor Bi Guo-Qiang, was made possible by a highly advanced imaging technique they developed called time-resolved cryo-electron tomography (cryo-ET). This method allowed them to visualize the incredibly fast and minuscule movements of synaptic vesicles with unprecedented clarity and temporal precision. By capturing the cellular machinery in action at distinct moments, they could create a stop-motion movie of the entire neurotransmission sequence.
Advanced Freezing and Imaging
The team’s innovative approach combined two key technologies. First, they used optogenetics, a technique that uses light to trigger neurons to fire an action potential, or nerve impulse, on command. This allowed them to precisely control the timing of the synaptic event they wanted to observe. Second, they paired this stimulation with an extremely fast plunge-freezing system. This device freezes the sample so rapidly that water molecules cannot form ice crystals, preserving the cellular structures in a near-native, glass-like state. By timing the plunge-freezing to occur at specific intervals after the light stimulation—from just a few milliseconds to 300 milliseconds—the researchers could capture high-resolution 3D snapshots of every step in the process.
Mapping the Vesicle’s Path
In their study, published in the journal Science, the researchers analyzed over 1,000 tomograms of cultured excitatory synapses from the hippocampus, a brain region critical for learning and memory. This vast collection of images provided a detailed map of the vesicle’s journey as it prepared to release its contents. By sorting the snapshots chronologically, the team could piece together a fluid and continuous sequence of events. This detailed timeline allowed them to identify a distinct and previously unknown intermediate step that fundamentally changes the understanding of synaptic function.
The Kiss-Shrink-Run Sequence
The analysis of the tomograms revealed a consistent three-phase process that reconciled the previous competing models. The sequence begins with a kiss, proceeds through a novel shrinking phase, and ends with a run, ensuring the vesicle can be efficiently recycled.
The Initial ‘Kiss’
Within an astonishingly brief 4 milliseconds of the neuron firing, the synaptic vesicle docks with the presynaptic membrane and forms a small, loose fusion pore. This initial connection is the “kiss,” a transient opening that allows neurotransmitters to begin flowing into the synaptic cleft. This observation confirms a key element of the long-hypothesized kiss-and-run model, demonstrating that vesicles can indeed release their contents without fully merging with the neuron’s membrane.
The Unexpected ‘Shrink’
Immediately following the kiss, the researchers observed a completely new phenomenon. The vesicle, still connected to the membrane, rapidly contracts, losing approximately half of its original surface area. This “shrink” phase is a critical discovery. It suggests a highly dynamic process where the vesicle actively expels its contents and changes its shape and size. This contraction is a far more active and dramatic step than the simple passive diffusion of neurotransmitters envisioned in older models.
The Efficient ‘Run’
After the vesicle shrinks, the fusion pore closes and the now-smaller vesicle detaches from the membrane, running back into the cytoplasm of the neuron. From there, it can be quickly refilled and prepared for another round of neurotransmission. This final step highlights the efficiency of the brain’s cellular machinery, allowing for the rapid and sustainable firing of synapses that is necessary for complex cognitive processes.
A New, Unified Framework
The kiss-shrink-run mechanism provides an elegant solution to the long-standing debate between full-collapse and kiss-and-run theories. It successfully integrates elements from both, creating a more comprehensive and accurate framework. The model confirms the transient pore opening of the kiss-and-run hypothesis while introducing the dynamic membrane alteration of the shrink phase, which accounts for the significant physical changes previously associated only with full collapse. It shows that the process is neither a complete, irreversible fusion nor a simple, passive kiss, but a sophisticated and controlled mechanical sequence.
This refined understanding has profound implications for neuroscience. Synaptic plasticity—the ability of synapses to strengthen or weaken over time—is the foundation of learning and memory, and it relies on the efficient recycling of synaptic vesicles. The kiss-shrink-run model provides a clearer picture of how synapses can sustain high rates of activity. Furthermore, many neurological and psychiatric disorders are thought to involve disruptions in synaptic communication. A more precise understanding of the fundamental mechanics of neurotransmission could help researchers identify what goes wrong in these conditions and potentially develop new therapeutic strategies targeting this process.
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