Exogenous nitric oxide causes potentiation of hippocampal synaptic transmission during low-frequency stimulation via the endogenous nitric oxide-cGMPpathway

Nitric oxide (NO) is a putative participant in synaptic plasticity and demo nstrations that exogenous NO can elicit the same plastic changes have been taken to support such a role. The experiments, carried out on the CA1 regio n of rat hippocampal slices, were aimed at testing this interpretation. A m ajor component of tetanus-induced long-term potentiation (LTP) was lost in response to L-nitroarginine, which inhibits NO synthase, and 1H-[1,2,4]oxad iazolo[4,3-a]quinoxalin-1-one (ODQ), which inhibits NO-sensitive soluble gu anylyl cyclase (sGC). At 0.2 Hz afferent fibre stimulation, exogenous NO pr oduced, concentration-dependently, a synaptic depression that reverted on w ashout to a persistent potentiation that occluded tetanus-induced LTP. The NO concentrations necessary (estimated in the 100-nM range), however, were mostly supramaximal for stimulating hippocampal slice sGC activity. Neverth eless the potentiation, but not the preceding depression, was blocked by OD Q. L-nitroarginine and an NMDA antagonist were similarly effective, indicat ing mediation by the endogenous NMDA receptor-NO synthase-sGC pathway. At a concentration normally too low to affect synaptic transmission but suffici ent to stimulate sGC (estimated to be 50 nM), exogenous NO reversed the eff ect of L-nitroarginine and caused a potentiation which was blocked by ODQ. At a concentration inducing the depression/potentiation sequence, NO partia lly inhibited hippocampal slice oxygen consumption. It is concluded that, a t physiological levels, exogenous NO can directly elicit a potentiation of synaptic transmission through sGC, provided that the synapses are suitably primed. At higher concentrations, NO inhibits mitochondrial respiration, wh ich can result in an enduring synaptic potentiation due to secondary activa tion of the endogenous NO-cGMP pathway.