Nitric oxide acts as a postsynaptic signaling molecule in calcium/calmodulin-induced synaptic potentiation in hippocampal CA1 pyramidal neurons

Postsynaptic injection of Ca2+/calmodulin (Ca2+/CaM) into hippocampal CA1 pyramidal neurons induces synaptic potentiation, which can occlude tetanus-induced potentiation (Wang and Kelly, 1995). Because Ca2+/CaM activates the major forms of nitric oxide synthase (NOS) to produce nitric oxide (NO), NO may play a role during Ca2+/CaM-induced potentiation. Here we show that extracellular application of the NOS inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) or postsynaptic co-injection of L-NAME with Ca2+/CaM blocked Ca2+/CaM-induced synaptic potentiation. Thus, NO is necessary for Ca2+/CaM-induced synaptic potentiation. In contrast, extracellular perfusion of membrane-impermeable NO scavengers N-methyl-D-glucamine dithiocarbamate/ferrous sulfate mixture (MGD-Fe) or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) did not attenuate Ca2+/CaM-induced synaptic potentiation, even though MGD-Fe or carboxy-PTIO blocked tetanus-induced synaptic potentiation. This result indicates that NO is not a retrograde messenger in Ca2+/CaM-induced synaptic potentiation. However, postsynaptic co-injection of carboxy-PTIO with Ca2+/CaM blocked Ca2+/CaM-induced potentiation. Postsynaptic injection of carboxy-PTIO alone blocked tetanus-induced synaptic potentiation without affecting basal synaptic transmission. Our results suggest that NO works as a postsynaptic (intracellular) messenger during Ca2+/CaM-induced synaptic potentiation.