Induction of hippocampal LTD requires nitric-oxide-stimulated PKG activityand Ca2+ release from cyclic ADP-ribose-sensitive stores

Long term depression (LTD) of synaptic transmission can be induced by sever al mechanisms, one thought to involve Ca2+-dependent activation of postsyna ptic nitric oxide (NO) synthase and subsequent diffusion of NO to the presy naptic terminal. We used the stable NO donor S-nitroso-N-acetylpenicillamin e (SNAP) to study the NO-dependent form of LTD at Schaffer collateral-CA1 s ynapses in vitro. SNAP (100 mu M) enhanced the induction of LTD via a casca de that was blocked by the N-methyl-D-aspartate receptor antagonist D-2-ami no-5-phosphonopentanoic acid (50 mu M), NO guanylyl cyclase inhibitor 1H-[1 ,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (10 mu M), and the PKG inhibitor KT5823 (1 mu M). We further show that LTD induced by low-frequency stimulat ion in the absence of SNAP also is blocked by KT5823 or Rp-8-(4-chloropheny lthio)-guanosine 3',5'-cyclic monophosphorothioate (10 mu M), cyclic guanos ine 3',5' monophosphate-dependent protein kinase (PKG) inhibitors with diff erent mechanisms of action. Furthermore SNAP-facilitated LTD was blocked wh en release from intracellular calcium stores was inhibited by ryanodine (10 mu M). Finally, two cell-permeant antagonists of the cyclic ADP-ribose bin ding site on ryanodine receptors also were able to block the induction of L TD. These results support a cascade for induction of homosynaptic, NO-depen dent LTD involving activation of guanylyl cyclase, production of guanosine 3',5' cyclic monophosphate and subsequent PKG activation. This process has an additional requirement for release of Ca2+ from ryanodine-sensitive stor es, perhaps dependent on the second-messenger cyclic ADP ribose.