Wilson Paxton, Kim Noah, Cotter Rachel, Parkes Mason, Cmelak Luca, Reed Miranda N, Gramlich Michael W
Department of Physics, Auburn University, Auburn, AL, USA.
Department of Psychological Sciences, Auburn University, Auburn, AL, USA.
Cell Rep. 2025 Apr 22;44(4):115410. doi: 10.1016/j.celrep.2025.115410. Epub 2025 Mar 26.
Synapses represent a fundamental unit of information transfer during cognition via presynaptic vesicle exocytosis. It has been established that evoked release is probabilistic, but the mechanisms behind spontaneous release are less clear. Understanding spontaneous release is vital, as it plays a key role in maintaining synaptic connections. We propose a model framework for spontaneous release where the reserve pool geometrically constrains recycling pool vesicles, creating an entropic force that drives spontaneous release rate. We experimentally support this framework using SEM, fluorescence microscopy, computational modeling, and pharmacological approaches. Our model correctly predicts the spontaneous release rate as a function of presynapse size. Finally, we use our approach to show how β-amyloid mutations linked to Alzheimer's disease lead to increased spontaneous release rates. These results indicate that synapses regulate the density of the recycling pool to control the spontaneous release rate and may serve as an early indicator of Alzheimer's disease.
突触是认知过程中通过突触前囊泡胞吐作用进行信息传递的基本单位。已经确定诱发释放是概率性的，但自发释放背后的机制尚不清楚。理解自发释放至关重要，因为它在维持突触连接中起关键作用。我们提出了一个自发释放的模型框架，其中储备池对循环池囊泡进行几何约束，产生一种驱动自发释放速率的熵力。我们使用扫描电子显微镜、荧光显微镜、计算建模和药理学方法对这一框架进行了实验支持。我们的模型正确地预测了自发释放速率作为突触前大小的函数。最后，我们用我们的方法展示了与阿尔茨海默病相关的β-淀粉样蛋白突变如何导致自发释放速率增加。这些结果表明，突触通过调节循环池的密度来控制自发释放速率，并且可能作为阿尔茨海默病的早期指标。
