Gallimore Andrew R, Hepburn Iain, Georgiev Svilen V, Rizzoli Silvio O, De Schutter Erik
Computational Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Germany.
Sci Adv. 2025 May 30;11(22):eadq6477. doi: 10.1126/sciadv.adq6477. Epub 2025 May 28.
Synaptic transmission is driven by a complex cycle of vesicle docking, release, and recycling, maintained by distinct vesicle pools. However, the partitioning of vesicle pools and reserve pool recruitment remain poorly understood. We use a novel vesicle modeling technology to model the synaptic vesicle cycle in unprecedented molecular and spatial detail at a hippocampal synapse. Our model demonstrates robust recycling of synaptic vesicles that maintains consistent synaptic release, even during sustained high-frequency firing. We also show how the cytosolic proteins synapsin-1 and tomosyn-1 cooperate to regulate recruitment of reserve pool vesicles during sustained firing to maintain transmission, as well as the potential of selective vesicle active zone tethering to ensure rapid vesicle replenishment while minimizing reserve pool recruitment. We also monitored vesicle usage in isolated hippocampal neurons using pH-sensitive pHluorin, demonstrating that reserve vesicle recruitment depends on firing frequency, even at nonphysiologically high firing frequencies, as predicted by the model.
突触传递由囊泡对接、释放和循环利用的复杂循环驱动，这一循环由不同的囊泡池维持。然而，囊泡池的划分和储备池募集仍知之甚少。我们使用一种新型囊泡建模技术，以前所未有的分子和空间细节对海马突触中的突触囊泡循环进行建模。我们的模型显示突触囊泡能够强劲地循环利用，即使在持续高频放电期间也能维持一致的突触释放。我们还展示了胞质蛋白突触结合蛋白-1和突触结合蛋白-1如何协同调节持续放电期间储备池囊泡的募集以维持传递，以及选择性囊泡活性区拴系在确保快速囊泡补充同时最小化储备池募集方面的潜力。我们还使用对pH敏感的pHluorin监测了分离的海马神经元中的囊泡使用情况，结果表明，正如模型所预测的那样，即使在非生理性高频放电频率下，储备囊泡的募集也取决于放电频率。
