A use-dependent increase in release sites drives facilitation at calretinin-deficient cerebellar parallel-fiber synapses.

Endogenous Ca(2+)-binding proteins affect synaptic transmitter release and short-term plasticity (STP) by buffering presynaptic Ca(2+) signals. At parallel-fiber (PF)-to-Purkinje neuron (PN) synapses in the cerebellar cortex loss of calretinin (CR), the major buffer at PF terminals, results in increased presynaptic Ca(2+) transients and an almost doubling of the initial vesicular releases probability (p r). Surprisingly, however, it has been reported that loss of CR from PF synapses does not alter paired-pulse facilitation (PPF), while it affects presynaptic Ca(2+) signals as well as p r. Here, we addressed this puzzling observation by analyzing the frequency- and Ca(2+)-dependence of PPF at unitary PF-to-PN synapses of wild-type (WT) and CR-deficient (CR(-/-)) mice using paired recordings and computer simulations. Our analysis revealed that PPF in CR(-/-) is indeed smaller than in the WT, to a degree, however, that indicates that rapid vesicle replenishment and recruitment of additional release sites dominate the synaptic efficacy of the second response. These Ca(2+)-driven processes operate more effectively in the absence of CR, thereby, explaining the preservation of robust PPF in the mutants.