ARACHIDONIC-ACID AND DIACYLGLYCEROL ACT SYNERGISTICALLY THROUGH PROTEIN-KINASE-C TO PERSISTENTLY ENHANCE SYNAPTIC TRANSMISSION IN THE HIPPOCAMPUS

In model membranes, arachidonic acid and diacylglycerol have been prop osed to synergistically induce a membrane-inserted, constitutively act ive form of protein kinase C. We have investigated the effects of thes e lipid protein kinase C activators on synaptic efficacy in the Schaff er collateral input to CA1 hippocampal pyramidal cells. Arachidonic ac id (5 mu M) perfusion combined with repetitive afferent stimulation ha d no consistent effect on field excitatory postsynaptic potentials rec orded in stratum radiatum, while treatment with a cell-permeable digly ceride, oleoyl-acetylglycerol (5 mu g/ml), followed by stimulation, le d to a short-term potentiation. By contrast, the combination of oleoyl -acetylglycerol and arachidonic acid gave rise to a long-lasting non-d ecremental potentiation of field excitatory postsynaptic potentials. T he induction of potentiation was ''activity dependent'', as there was either no significant effect or there was a measurable depression when repetitive synaptic stimulation was omitted. Furthermore, consistent with a protein kinase C-dependent process, the potentiation was blocke d by the kinase inhibitors H-7 and staurosporine. The results suggest that relatively low concentrations of arachidonic acid and diacylglyce rol work synergistically through protein kinase C to persistently enha nce synaptic transmission. This synergy has the makings of an associat ive (Hebbian) device for long-term potentiation induction operating at the second messenger level.