The role of the cAMP pathway in LTP was studied in the CAI region of hippocampus. Widely spaced trains of high frequency stimulation generated cAMP postsynaptically via NMDA receptors and calmodulin, consistent with the Ca2+/calmodulin-mediated stimulation of postsynaptic adenylyl cyclase. The early phase of LTP produced by the same pattern of high frequency stimulation was dependent an postsynaptic cAMP, However, synaptic transmission was not increased by postsynaptic application of cAMP. Early LTP became cAMP-independent when protein phosphatase inhibitors were injected postsynaptically. These observations indicate that in early LTP the cAMP signaling pathway, instead of transmitting signals for the generation of LTP, gates LTP through postsynaptic protein phosphatases.