Nitric-oxide-guanylyl-cyclase-dependent and -independent components of multiple forms of long-term synaptic depression

Hippocampus. 1997;7(3):286-95. doi: 10.1002/(SICI)1098-1063(1997)7:3<286::AID-HIPO4>3.0.CO;2-J.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cyclic GMP / analogs & derivatives
  • Cyclic GMP / pharmacology
  • Electrophysiology
  • Enzyme Inhibitors / pharmacology
  • Guanylate Cyclase / metabolism*
  • Hippocampus / chemistry
  • Hippocampus / drug effects
  • Hippocampus / enzymology*
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Male
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Niacinamide / pharmacology
  • Nitric Oxide / metabolism*
  • Organ Culture Techniques
  • Oxadiazoles / pharmacology
  • Penicillamine / analogs & derivatives
  • Penicillamine / pharmacology
  • Platelet Aggregation Inhibitors / pharmacology
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • S-Nitroso-N-Acetylpenicillamine
  • Synapses / chemistry
  • Synapses / enzymology
  • Thionucleotides / pharmacology

Substances

  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • Enzyme Inhibitors
  • Oxadiazoles
  • Platelet Aggregation Inhibitors
  • Quinoxalines
  • Thionucleotides
  • Niacinamide
  • Nitric Oxide
  • 8-((4-chlorophenyl)thio)cyclic-3',5'-GMP
  • S-Nitroso-N-Acetylpenicillamine
  • Guanylate Cyclase
  • Penicillamine
  • Cyclic GMP