Long-term potentiation in the hippocampal CA1 region of mice lacking cGMP-dependent kinases is normal and susceptible to inhibition of nitric oxide synthase.
Long-term potentiation (LTP) is a potential cellular mechanism for learning and memory. The retrograde messenger nitric oxide (NO) is thought to induce LTP in the CA1 region of the hippocampus via activation of soluble guanylyl cyclase (sGC) and, ultimately, cGMP-dependent protein kinase (cGK). Two genes code for the isozymes cGKI and cGKII in vertebrates. The functional role of cGKs in LTP was analyzed using mice lacking the gene(s) for cGKI, cGKII, or both. LTP was not altered in the mutant mice lineages. However, LTP was reduced by inhibition of NO synthase and NMDA receptor antagonists, respectively. The reduced LTP was not recovered by the cGK-activator 8-(4 chlorophenylthio)-cGMP. Moreover, LTP was not affected by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]-quiloxalin-1-one. In contrast, it was effectively suppressed by nicotinamide, a blocker of the ADP-ribosyltransferase. These results show that cGKs are not involved in LTP in mice and that NO induces LTP through an alternative cGMP-independent pathway, possibly ADP-ribosylation.
Kleppisch
T
T
Institut für Pharmakologie und Toxikologie, 80802 München, Germany.
Pfeifer
A
A
Klatt
P
P
Ruth
P
P
Montkowski
A
A
Fässler
R
R
Hofmann
F
F
D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000172:deficiency*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010069:Oxadiazoles / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012016:Reference Values; D009435:Synaptic Transmission / Q000187:drug effects
C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases