Chemically induced, activity-independent LTD elicited by simultaneous activation of PKG and inhibition of PKA

Although it is widely agreed that cyclic AMP is necessary for the full expr ession of long-term potentiation of synaptic strength, it is unclear whethe r cyclic AMP or cyclic AMP-dependent protein kinase (PKA) play roles in the induction of long-term depression (LTD). We show here that two PKA inhibit ors, H-89 (10 mu M) and KT5720 (1 mu M), are unable to block induction of L TD at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Rath er, H-89 enhanced the magnitude of LTD induced by submaximal low-frequency stimulation. Raising [cGMP] with zaprinast (20 mu M), a selective type V ph osphodiesterase inhibitor, reversibly depressed synaptic potentials. Howeve r, coapplication of H-89 plus zaprinast converted this to a robust LTD that depended critically on activation of cyclic GMP-dependent protein kinase ( PKG). Chemically induced LTD is activity-independent because it could be in duced without stimulation and in tetrodotoxin (0.5 mu M). Additionally, che mical LTD did not require activation of N-methyl-D-aspartate or GABA recept ors and could be reversed by LTP. Stimulus-induced LTD occluded chemical LT D, suggesting, a common expression mechanism. In contrast to bath applicati on, postsynaptic infusion of H-89 into CA1 pyramidal neurons did not enhanc e LTD, suggesting a presynaptic site of action. Further evidence for a pres ynaptic locus was supplied by experiments where H-89 applied postsynaptical ly along with bath application of zaprinast was unable to produce chemical LTD. Thus simultaneous presynaptic generation of cyclic GMP and inhibition of PKA is sufficient to induce LTD of synaptic transmission at Schaffer col lateral-CA1 synapses.