Vesicle exocytosis is mediated by the complex interaction between synaptic vesicle and plasma membrane proteins, many of which are substrates for protein kinases. Exogenous protein kinase activators increase release probability at several mammalian CNS synapses, but the physiological conditions under which presynaptic protein kinases become activated are not known. We report here that calcium/phospholipid-dependent protein kinase C (PKC) is activated by high-frequency stimulation and mediates post-tetanic potentiation (PTP) in the rat hippocampus.