Calcium influx through NMDA receptors (NMDARs) is critical to some forms of synaptic plasticity. By modulating NMDAR function, different kinases can regulate induction of long-term potentiation (LTP). Although cAMP-dependent signaling has been implicated in the early phase of NMDAR-dependent LTP, the precise molecular mechanism is unknown. It has recently been suggested that phosphorylation by PKA selectively enhances NMDARs Ca2+ permeability (V.A. Skeberdis et al; SFN. Abstract 261.3, 2001), a mechanism that may be relevant to LTP induction. Here, we examined the effect of PKA inhibition on the early phase of NMDAR-dependent LTP at Schaffer collateral-CA1 synapses in acute mouse hippocampal slices and directly monitored calcium influx into CA1 pyramidal cell spines by two-photon imaging. Bath application of the PKA inhibitors H-89 or PKI 30 min before tetanic stimulation markedly reduced the magnitude of early LTP, with no effect on previously established LTP or basal synaptic transmission. As expected if...