ROLE OF GUANYLYL CYCLASE AND CGMP-DEPENDENT PROTEIN-KINASE IN LONG-TERM POTENTIATION

SEVERAL lines of evidence suggest that cyclic GMP might be involved in long-term potentiation (LTP) in the hippocampus1-6. Arachidonic acid, nitric oxide and carbon monoxide, three molecules that have been prop osed to act as retrograde messengers in LTP7-9, all activate soluble g uanylyl cyclase1,10,11. We report here that an inhibitor of guanylyl c yclase blocks the induction of LTP in the CA1 region of hippocampal sl ices. Conversely, cGMP analogues produce long-lasting enhancement of t he excitatory postsynaptic potential if they are applied at the same t ime as weak tetanic stimulation of the presynaptic fibres. The enhance ment is spatially restricted, is not blocked by valeric acid (APV), ni fedipine, or picrotoxin, and partially occludes LTP. This synaptic enh ancement may be mediated by the cGMP-dependent protein kinase (PKG). I nhibitors of PKG block the induction of LTP, and activators of PKG pro duce activity-dependent long-lasting enhancement. These results sugges t that guanylyl cyclase and PKG contribute to LTP, possibly as activit y-dependent presynaptic effectors of retrograde messengers.