Presynaptic recycling pool density regulates spontaneous synaptic vesicle exocytosis rate and is upregulated in the presence of β-amyloid

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.