Ca(2+) is thought to be essential for the exocytosis and endocytosis of synaptic vesicles. However, the manner in which Ca(2+) coordinates these processes remains unclear, particularly at mature synapses. Using membrane capacitance measurements from calyx of Held nerve terminals in rats, we found that vesicle endocytosis is initiated primarily in Ca(2+) nanodomains around Ca(2+) channels, where exocytosis is triggered. Bulk Ca(2+) outside of the domain could also be involved in endocytosis at immature synapses, although only after extensive exocytosis at more mature synapses. This bulk Ca(2+)-dependent endocytosis required calmodulin and calcineurin activation at immature synapses, but not at more mature synapses. Similarly, GTP-independent endocytosis, which occurred after extensive exocytosis at immature synapses, became negligible after maturation. We propose that nanodomain Ca(2+) simultaneously triggers exocytosis and endocytosis of synaptic vesicles and that the molecular mechanisms underlying Ca(2+)-dependent endocytosis undergo major developmental changes at this fast central synapse.