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Synaptic ribbons are thought to provide vesicles for continuous release in some retinal nonspiking neurons, yet recent studies indicate that genetic removal of the ribbon has little effect on release kinetics. To investigate vesicle replenishment at synaptic ribbons, we used total internal reflection fluorescence microscopy to image synaptic vesicles and ribbons in retinal bipolar cells of goldfish ( Carassius auratus ) of both sexes. Analysis of vesicles released by trains of 30 ms depolarizations revealed that most releasable vesicles reside within 300 nm of the ribbon center. A single 30 ms step to 0 mV was sufficient to deplete the membrane-proximal vesicle pool, while triggering rapid stepwise movements of distal vesicles along the ribbon and toward the plasma membrane. Replenishment only becomes rate-limiting for recovery from paired-pulse depression for interstimulus intervals shorter than 250 ms. For longer interstimulus intervals, vesicle movement down the ribbon is fast enough to replenish released vesicles, but newly arrived vesicles are not release-ready. Notably, the rates of vesicle resupply and maturation of newcomers are among the fastest measured optically at any synapse. Lastly, our data show that the delay in vesicle departure increases and vesicle speed decreases with multiple stimuli. Our results support a role for ribbons in the supply of vesicles for release, provide direct measurements of vesicle movement down the ribbon, and suggest that multiple factors contribute to paired-pulse depression. SIGNIFICANCE STATEMENT Synaptic ribbons are macromolecular scaffolds that tether synaptic vesicles close to release sites in nonspiking neurons of the retina and cochlea. Because these neurons release neurotransmitter continuously, synaptic ribbons are assumed to act as platforms for supplying vesicles rapidly in the face of prolonged stimulation. Yet, ribbon synapses suffer from profound paired-pulse depression, which takes seconds to subside. We investigated the mechanistic origin of this phenomenon by directly imaging triggered vesicle movement and release at ribbon sites in retinal bipolar cells, and find that, although ribbon synapses deliver and prime vesicles faster than most conventional synapses, both vesicle absence and vesicle priming contribute to the long recovery from paired-pulse depression.

Direct Observation of Vesicle Transport on the Synaptic Ribbon Provides Evidence That Vesicles Are Mobilized and Prepared Rapidly for Release