The specific role of cGMP in hippocampal LTP

Previous results have suggested that cGMP is involved in hippocampal long-t erm potentiation (LTP), perhaps as the presynaptic effector of a retrograde messenger. However, other studies have failed to replicate some of those r esults, making the role of cGMP uncertain. We therefore reexamined this que stion and identified several variables that can affect the contribution of cGMP. First, brief perfusion with 8-Br-cGMP before weak tetanic stimulation produced long-lasting potentiation in the CA1 region of hippocampal slices , but more prolonged perfusion with 8-Br-cGMP before the tetanus did not pr oduce long-lasting potentiation. Second, the activity-dependent long-lastin g potentiation by cGMP analogs was reduced when NMDA receptors were complet ely blocked, indicating that NMDA receptor activation contributes to, but i s not required for, the potentiation. The amount of reduction of the potent iation differed with different protocols, and in some cases could be comple te. Third, LTP produced by strong tetanic stimulation in the stratum radiat um of CAI (which expresses eNOS) was blocked by inhibitors of soluble guany lyl cyclase or cGMP-dependent protein kinase, but LTP in the stratum oriens (which does not express eNOS) was not. The results of these experiments sh ould. help to explain some of the discrepant findings from previous studies , and, in addition, may provide insights into the mechanisms and functional role of the cGMP-dependent component of LTP.