It has been demonstrated that stimulation of protein kinase A (PKA) results in enhanced synaptic transmission in the hippocampus and other brain areas. To investigate mechanisms of the PKA-mediated potentiation of synaptic transmission, we used rat hippocampal embryonic cultures. In low-density cultures, paired recordings under the perforated patch demonstrated that 15 min forskolin treatment produced long-lasting potentiation of evoked EPSCs (eEPSCs) mediated by the cAMP/PKA pathway. eEPSC amplitudes increased to 240±10 % of baseline after 15 min of forskolin treatment (early potentiation). After forskolin washout, eEPSCs declined to a potentiated level. Potentiation was sustained for at least 85 min after forskolin washout and, 60 min after forskolin washout, constituted 152±7% of baseline (late potentiation). Disruption of presynaptic processes with the whole-cell configuration and internal solution containing PKA inhibitor peptide did not affect forskolin-induced potentiation. Disruption of postsynaptic processes, in contrast, impaired early potentiation and abolished late potentiation. Study of mEPSCs confirmed the contribution of postsynaptic mechanisms. Forskolin-induced enhancement of mEPSC frequency observed under the perforated patch was attenuated by the whole-cell configuration. Forskolin also induced an increase of mEPSC amplitudes in the perforated patch, but not in the whole-cell, experiments. Potentiation of eEPSCs was not activity dependent, persisting in the absence of stimulation. NMDA receptor blockade did not abolish forskolin-induced potentiation. In summary, we demonstrate that forskolin-induced potentiation of eEPSCs was mediated by postsynaptic mechanisms, presumably via upregulation of AMPA receptors by phosphorylation.