title: Nitric-oxide-guanylyl-cyclase-dependent and -independent components of multiple forms of long-term synaptic depression.
abstract: Long-term depression (LTD) of synaptic strength is induced by glutamate-triggered increases in postsynaptic [Ca2+], through either influx or release from intracellular stores. Induction of LTD has also been reported to require release of Ca2+ from presynaptic stores and activation of presynaptic Ca2+/calmodulin-dependent protein kinase II. This finding leads to the hypothesis that the intercellular messenger nitric oxide (NO) may be a means by which postsynaptic Ca2+ triggers changes expressing LTD in presynaptic terminals. We report that bath application of the oxadiazoloquinoxalone derivative ODQ (4 microM), a selective inhibitor of NO-sensitive guanylyl cyclase (NOGC), markedly attenuated (90%) the magnitude of LTD induced by low-frequency stimulation (LFS; 1 Hz/15 min) of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Both the NO donor S-nitroso-N-acetylpenicillamine (100 microM) and the membrane-permeant cyclic guanine 3',5'-monophosphate (cGMP) analogue 8-(-4-chlorophenylthio) guanosine (8-pCPT)-cGMP (50 microM) enhanced the magnitude of LTD, which is consistent with he hypothesis that activation of NOGC plays a role in the induction of LTD. Nicotinamide (20 mM), an inhibitor of NO-activated ADP ribosyltransferase, did not impair the induction of LTD. In contrast to de novo LTD, the reversal of long-term potentiation by LFS (depotentiation) was only partially blocked (55%) by ODQ, and heterosynaptic LTD was not impaired at all, suggesting that there are both NOGC-dependent and -independent forms of LTD. Because postsynaptic intracellular infusion of ODQ (500 microM) failed to block the induction of LTD, we conclude that activation of presynaptic NOGC is a necessary step in the induction of an NOGC-dependent component of LTD.
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461-1602, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Gage
authors.forename: M
authors.initials: M
authors.lastname: Reyes
authors.forename: P K
authors.initials: PK
authors.lastname: Stanton
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009536:Niacinamide / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009924:Organ Culture Techniques; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D013569:Synapses / Q000737:chemistry / Q000201:enzymology; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D011810:Quinoxalines; D013873:Thionucleotides; D009536:Niacinamide; D009569:Nitric Oxide; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D026423:S-Nitroso-N-Acetylpenicillamine; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP