Variance-mean analysis in the presence of a rapid antagonist indicates vesicle depletion underlies depression at the climbing fiber synapse.

Many types of synapses throughout the nervous system are transiently depressed during high-frequency stimulation. Several mechanisms have been proposed to account for this depression, including depletion of release-ready vesicles. However, numerous studies have raised doubts about the importance of depletion in depression of central synapses and have implicated alternative mechanisms, such as decreased release probability. We use variance-mean analysis to determine the mechanism of depression at the climbing fiber to Purkinje cell synapse. We find that postsynaptic receptor saturation makes it difficult to distinguish between a decrease in available vesicles and a reduction in release probability. When AMPA receptor saturation is relieved with a low-affinity antagonist, variance-mean analysis reveals that depression arises from a decrease in the number of release-ready vesicles. Vesicle depletion is prominent, despite numerous docked vesicles at each release site, due to multivesicular release. We conclude that vesicle depletion can contribute significantly to depression of central synapses.