Traffic jams during vesicle cycling lead to synaptic depression.

During prolonged stimulation, fusion of thousands of synaptic vesicles poses a challenge for the temporal and spatial coordination of exocytosis and endocytosis. In this issue of Neuron, Hosoi and colleagues reveal that Ca2+-microdomains trigger compensatory endocytosis. Block of endocytosis enhances short-term depression by delaying vesicle recruitment to docking sites on active zones.