Attenuation of paired-pulse facilitation associated with synaptic potentiation mediated by postsynaptic mechanisms. J. Neurophysiol. 78: 2707-2716, 1997. The relationship between paired-pulse facilitation (PPF) and synaptic potentiation induced by various protocols and their cellular and molecular mechanisms were examined by extracellular field potential and current- or voltage-clamp recordings at CA1 synapses in rat hippocampal slices. Microelectrodes were used for both intracellular recordings and injections of modulators of calcium (Ca2+) and Ca2+/calmodulin (CaM) signaling pathways into postsynaptic neurons. Basal synaptic transmission was not accompanied by changes in PPF. Tetanic stimulation induced long-term potentiation (LTP) of synaptic transmission and attenuated PPF. Experiments stimulating two independent Schaffer collateral/commisural(S/C) pathways showed that PPF attenuation and tetanus-LTP were pathway specific. Postsynaptic injections of pseudosubstrate inhibitors of CaM-dependent protein kinase II and protein kinase C (CaM-KII/PKC), [Ala286]CaMKII286-302 plus PKC19-31, almost completely attenuated tetanus-LTP and reversed PPF attenuation but did not affect synaptic transmission and PPF under basal conditions. Postsynaptic injections of heparin and dantrolene (inhibitors of IP3 and ryanodine receptors at intracellular Ca2+ stores) prevented tetanus-LTP induction and PPF attenuation. Postsynaptic injections of calcineurin (CaN) inhibitors, CaN autoinhibitory peptide (CaN-AIP) or FK-506, enhanced synaptic transmission and decreased PPF. CaN-inhibited synaptic potentiation and PPF attenuation were unaffected by (-)-a-Amino-5-phosphonopentanoic, but blocked by coinjecting 1, 2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, heparin plus dantrolene, calmodulin-binding peptide, or [Ala286]CaMKII281-302 plus PKC19-31. PPF attenuation associated with tetanus-LTP or CaN-inhibited synaptic potentiation resulted from smaller increases in the potentiation of the second synaptic responses (R2) compared with the potentiation of the first responses (R1). Our results indicate that PPF attenuation is associated with synaptic potentiation mediated by postsynaptic mechanisms, and postsynaptic Ca2+/CaM signaling pathways play a dual role in synaptic plasticity. CaN activity limits synaptic transmission under basal conditions, whereas the activation of Ca2+-dependent protein kinases enhances synaptic transmission and attenuates PPF at central synapses.