To study how the late phase of long-term potentiation (LTP) in hippocampus arises, we examined the resulting LTP for its time course and its dependence on protein synthesis and different second-messenger kinases by applying various conditioning tetani. We find that one high-frequency train (100 Hz) produces a form of LTP that lasts longer than 1 hr but less than 3 hr (the early phase of LTP, or E-LTP). It is blocked by inhibitors of calcium/calmodulin kinase II (Cam kinase II) but is not affected by an inhibitor of cAMP-dependent protein kinase [protein kinase A (PKA) and the protein synthesis inhibitor anisomycin] nor is it occluded by the cAMP activator forskolin. In contrast, when three high-frequency trains are used, the resulting potentiation persists for at least 6-10 hr. The L-LTP induced by three trains differs from the E-LTP in that it requires new protein synthesis, is blocked by an inhibitor of cAMP-dependent protein kinase, and is occluded by forskolin. These results indicate that the two mechanistically distinctive forms of LTP, a transient, early component (E-LTP) and a more enduring form (L-LTP), can be recruited selectively by changing the number of conditioning tetanic trains. Repeated tetani induce a PKA and protein synthesis-dependent late component that adds to the amplitude and duration of the potentiation induced by a single tetanus.