title: Evidence for involvement of the cGMP-protein kinase G signaling system in the induction of long-term depression, but not long-term potentiation, in the dentate gyrus in vitro.
abstract: The involvement of the cGMP-protein kinase G (PKG) signaling pathway in the induction of long-term depression (LTD) and long-term potentiation (LTP) was investigated in the medial perforant path of the dentate gyrus in vitro. Low-frequency stimulation (LFS)-induced LTD of field EPSPs was inhibited by bath perfusion of the selective soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3, -a]quinoxalin-1-one (ODQ). LFS-induced LTD of EPSPs and whole-cell patch-clamped EPSCs was also blocked by bath perfusion and postsynaptic intracellular injection, respectively, of the selective PKG inhibitor KT5823. Elevation of intracellular cGMP by perfusion of the cGMP phosphodiesterase inhibitor zaprinast resulted in induction of LTD of field EPSPs and EPSCs. Occlusion experiments showed mutual inhibition between LFS-induced LTD and zaprinast-induced LTD. The zaprinast-induced LTD of field EPSPs was inhibited by perfusion of ODQ and KT5823. In addition, zaprinast-induced LTD of EPSCs was inhibited by postsynaptic application of KT5823. Glutamate receptor stimulation, especially that of metabotropic glutamate receptors (mGluRs), was required for zaprinast-induced LTD, because cessation of test stimulation or perfusion with the mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) inhibited zaprinast-induced LTD. No inhibitory effect of ODQ or KT5823 on the induction of LTP of EPSPs or EPSCs was found. These data indicate that the cGMP-guanyly cyclase-PKG signaling pathway in the dentate gyrus is essential for induction of LTD, although not of LTP, in the dentate gyrus.
authors.affiliation: Department of Physiology, Trinity College, Dublin 2, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: M J
authors.initials: MJ
authors.lastname: Rowan
authors.forename: R
authors.initials: R
authors.lastname: Anwyl
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002227:Carbazoles; D006152:Cyclic GMP / Q000378:metabolism*; D018891:Dentate Gyrus / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007211:Indoles; D017774:Long-Term Potentiation / Q000502:physiology*; D009474:Neurons / Q000737:chemistry / Q000201:enzymology; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000470:Alkaloids; D001565:Benzoates; D002227:Carbazoles; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011810:Quinoxalines; D018094:Receptors, Metabotropic Glutamate; C073601:KT 5823; C079694:alpha-methyl-4-carboxyphenylglycine; D011494:Protein Kinases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D019204:GTP-Binding Proteins; D006162:Guanylate Cyclase; C011145:zaprinast; D006152:Cyclic GMP; D005998:Glycine