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

Paolo Calabresi, Paolo Gubellini, Diego Centonze, Giuseppe Sancesario, Maria Morello, Mauro Giorgi, Antonio Pisani, Giorgio Bernardi

Research output: Contribution to journalArticlepeer-review


High-frequency stimulation (HFS) of corticostriatal glutamatergic fibers induces 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 analysis shows that most of the striatal cGMP PDE activity is calmodulin-dependent and inhibited by zaprinast. The zaprinast-induced LTD occludes further depression by tetanic stimulation and vice versa. Both forms of synaptic plasticity 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. Accordingly, intracellular cGMP, activating protein kinase G (PKG), also induces LTD. Nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 7-nitroindazole monosodium salt (7-NINA) block LTD induced by either HFS or zaprinast, but not that induced by cGMR LTD is also induced by the NO donors s-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine. SNAP- induced LTD occludes further depression by HFS or zaprinast, and it is blocked by intracellular ODQ but not by L-NAME. Intracellular application of PKG inhibitors blocks LTD induced by HFS, zaprinast, and 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 demonstration that the NO/cGMP pathway exerts a feed-forward control on the corticostriatal synaptic plasticity.

Original languageEnglish
Pages (from-to)2489-2499
Number of pages11
JournalJournal of Neuroscience
Issue number7
Publication statusPublished - Apr 1 1999


  • Calmodulin-dependent phosphodiesterases
  • Electron microscopy
  • Intracellular recordings
  • Nitric oxide synthase
  • Striatum
  • Zaprinast

ASJC Scopus subject areas

  • Neuroscience(all)


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