A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression

High-frequency stimulation (HFS) of corticostriatal glutamatergic fibers in duces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of LTD can be mimicked by zaprinast , a selective inhibitor of cGMP phosphodiesterases (PDEs). Biochemical anal ysis shows that most of the striatal cGMP PDE activity is calmodulin-depend ent and inhibited by zaprinast. The zaprinast-induced LTD occludes further depression by tetanic stimulation and vice versa. Both forms of synaptic pl asticity are blocked by intracellular 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin -1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, indicating that an increased cGMP production in the spiny neuron is a key step. Accor dingly, intracellular cGMP, activating protein kinase G (PKG), also induces LTD. Nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl e ster hydrochloride (L-NAME) and 7-nitroindazole monosodium salt (7-NINA) bl ock LTD induced by either HFS or zaprinast, but not that induced by cGMP. L TD is also induced by the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine. SNAP-induced LTD occludes further depression by HFS or z aprinast, and it is blocked by intracellular ODQ but not by L-NAME Intracel lular application of PKG inhibitors blocks LTD induced by HFS, zaprinast, a nd SNAP. Electron microscopy immunocytochemistry shows the presence of NOS- positive terminals of striatal interneurons forming synaptic contacts with dendrites of spiny neurons. These findings represent the first demonstratio n that the NO/cGMP pathway exerts a feed-forward control on the corticostri atal synaptic plasticity.