Sequential activation of soluble guanylate cyclase, protein kinase G and cGMP-degrading phosphodiesterase is necessary for proper induction of long-term potentiation in CA1 of hippocampus Alterations in hyperammonemia

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission efficacy and is considered the base for some forms of learning and memory. Nitric oxide (NO)-induced formation of cGMP is involved in hippocampal LTP. We have studied in hippocampal slices the effects of application of a tetanus to induce LTP on cGMP metabolism and the mechanisms by which cGMP modulates LTP. Tetanus application induced a transient rise in cGMP, reaching a maximum at 10s and decreasing below basal levels 5 min after the tetanus, remaining below basal levels after 60 min. Soluble guanylate cyclase (sGC) activity increased 5 min after tetanus and returned to basal levels at 60 min. The decrease in cGMP was due to sustained tetanus-induced increase in cGMP-degrading phosphodiesterase activity, which remained activated 60 min after tetanus. Tetanus-induced activation of PDE and decrease of cGMP were prevented by inhibiting protein kinase G (PKG). This indicates that the initial increase in cGMP activates PKG that phosphorylates (and activates) cGMP-degrading PDE, which, in turn, degrades cGMP. Inhibition of sGC, of PKG or of cGMP-degrading phosphodiesterase impairs LTP, indicating that proper induction of LTP involves transient activation of sGC and increase in cGMP, followed by activation of cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading phosphodiesterase, resulting in long-lasting reduction of cGMP content. Hyperammonemia is the main responsible for the neurological alterations found in liver disease and hepatic encephalopathy, including impaired intellectual function. Hyperammonemia impairs LTP in hippocampus by altering the modulation of this sGC-PKG-cGMP-degrading PDE pathway. Exposure of hippocampal slices to 1 mM ammonia completely prevents tetanus-induced decrease of cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. This impairment is responsible for the loss of the maintenance of LTP in hyperammonemia, and may be also involved in the cognitive impairment in patients with hyperammonemia and hepatic encephalopathy.

[1]  J. Corbin,et al.  ANF elicits phosphorylation of the cGMP phosphodiesterase in vascular smooth muscle cells. , 1998, American journal of physiology. Heart and circulatory physiology.

[2]  V. Felipo,et al.  Hyperammonemia Impairs NMDA Receptor-Dependent Long-Term Potentiation in the CA1 of Rat Hippocampus In Vitro , 2000, Neurochemical Research.

[3]  P. Chapman,et al.  Nitric oxide synthase inhibitors block long-term potentiation induced by weak but not strong tetanic stimulation at physiological brain temperatures in rat hippocampal slices , 1993, Neuroscience Letters.

[4]  D. Lovinger,et al.  Translocation of protein kinase C activity may mediate hippocampal long-term potentiation. , 1986, Science.

[5]  R. Hawkins,et al.  Presynaptic Role of cGMP-Dependent Protein Kinase during Long-Lasting Potentiation , 2001, The Journal of Neuroscience.

[6]  J. Sweatt,et al.  Nitric oxide synthase-independent long-term potentiation in area CA1 of hippocampus. , 1993, Neuroreport.

[7]  R. Butterworth,et al.  Neurobiology of ammonia , 2002, Progress in Neurobiology.

[8]  V. Felipo,et al.  Chronic Moderate Hyperammonemia Impairs Active and Passive Avoidance Behavior and Conditional Discrimination Learning in Rats , 2000, Experimental Neurology.

[9]  J. Corbin,et al.  Substrate- and kinase-directed regulation of phosphorylation of a cGMP-binding phosphodiesterase by cGMP. , 1990, The Journal of biological chemistry.

[10]  B. Fleshler,et al.  The Liver: Biology and Pathobiology , 1983 .

[11]  A. Carrel.  Transplantation of the kidney with implantation of the renal vessels in the aorta and vena cava , 1906 .

[12]  Charles R.scriver,et al.  The Metabolic basis of inherited disease , 1989 .

[13]  J. Zwiller,et al.  Activation of soluble guanylate cyclase through phosphorylation by protein kinase C in intact PC12 cells. , 1993, Biochimica et biophysica acta.

[14]  S. Brusilow,et al.  Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. , 1984, The New England journal of medicine.

[15]  Aryeh Routtenberg,et al.  Protein kinase C inhibitors eliminate hippocampal long-term potentiation , 1987, Brain Research.

[16]  V. Felipo,et al.  Long-Term Potentiation in Hippocampus Involves Sequential Activation of Soluble Guanylate Cyclase, cGMP-Dependent Protein Kinase, and cGMP-Degrading Phosphodiesterase , 2002, The Journal of Neuroscience.

[17]  J. Zwiller,et al.  Protein kinase C catalyzes phosphorylation of guanylate cyclase in vitro. , 1985, The Journal of biological chemistry.

[18]  H. Schulman,et al.  An ADP-ribosyltransferase as a potential target for nitric oxide action in hippocampal long-term potentiation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Garthwaite,et al.  Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase , 1995, Neuroscience.

[20]  J. Finn,et al.  Hepatic encephalopathy in cattle. , 1974, The Cornell veterinarian.

[21]  Wei-Yang Lu,et al.  Activation of Synaptic NMDA Receptors Induces Membrane Insertion of New AMPA Receptors and LTP in Cultured Hippocampal Neurons , 2001, Neuron.

[22]  D. Muller,et al.  Blockade of long-term potentiation and of NMDA receptors by the protein kinase C antagonist calphostin C , 1993, Naunyn-Schmiedeberg's Archives of Pharmacology.

[23]  J. Corbin,et al.  Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. , 2000, European journal of biochemistry.

[24]  R. Iyengar,et al.  Postsynaptic CAMP pathway gates early LTP in hippocampal CA1 region , 1995, Neuron.

[25]  E. Kandel,et al.  Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation , 1994, Nature.

[26]  R. Nicoll,et al.  Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus. , 1996, Learning & memory.

[27]  E. Kandel,et al.  Nitric Oxide Signaling Contributes to Late-Phase LTP and CREB Phosphorylation in the Hippocampus , 1999, The Journal of Neuroscience.

[28]  V. Felipo,et al.  Hyperammonemia impairs long-term potentiation in hippocampus by altering the modulation of cGMP-degrading phosphodiesterase by protein kinase G , 2004, Neurobiology of Disease.

[29]  E. Kandel,et al.  Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[30]  G. Böhme,et al.  Possible involvement of nitric oxide in long-term potentiation. , 1991, European journal of pharmacology.

[31]  P. Andersen,et al.  Protein kinase C injection into hippocampal pyramidal cells elicits features of long term potentiation , 1987, Nature.

[32]  J. Zwiller,et al.  Evidence for phosphorylation of rat brain guanylate cyclase by cyclic AMP-dependent protein kinase. , 1981, Biochemical and biophysical research communications.

[33]  R. Anwyl,et al.  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 , 1998, The Journal of Neuroscience.

[34]  P. Ott,et al.  Cerebral herniation in patients with acute E liver failure is correlated with arterial ammonia concentration , 1999, Hepatology.

[35]  V. Felipo,et al.  Chronic hyperammonemia impairs the glutamate–nitric oxide–cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo , 1998, The European journal of neuroscience.

[36]  D. Madison,et al.  A requirement for the intercellular messenger nitric oxide in long-term potentiation. , 1991, Science.

[37]  R. Anwyl,et al.  The selective neuronal NO synthase inhibitor 7-nitro-indazole blocks both long-term potentiation and depotentiation of field EPSPs in rat hippocampal CA1 in vivo , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.