Abstract
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. Hyperammonemia impairs LTP in hippocampus. Proper LTP induction in hippocampal slices requires activation of the soluble guanylate cyclase (sGC)-protein kinase G (PKG)-cyclic guanosine monophosphate (cGMP)-degrading phosphodiesterase pathway. Hyperammonemia impairs LTP by impairing the tetanus-induced activation of this pathway. The tetanus induces a rapid cGMP rise, reaching a maximum at 10 s, both in the absence or in the presence of ammonia. The increase in cGMP is followed, in control slices, by a sustained decrease in cGMP because of PKG-mediated activation of cGMP-degrading phosphodiesterase, which is required for maintenance of LTP. Hyperammonemia prevents completely tetanus-induced decrease in cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. Addition of 8Br-cGMP to slices treated with ammonia restores both phosphodiesterase activation and maintenance of LTP. Impairment of LTP in hyperammonemia may be involved in the impairment of the cognitive function in patients with hepatic encephalopathy.
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References
Akers, R.F., Lovinger, D.M., Colley, P.A., Linden, D.J., and Routtenberg, A. (1986). Translocation of protein kinase C activity may mediate hippocampal long-term potentiation. Science 231:587–589.
Blitzer, R.D., Wong, T., Nouranifar, R., Iyengar, R., and Landau, E.M. (1995). Postsynapyic cAMP pathway gates early LTP in hippocampal CA1 region. Neuron 15:1403–1414.
Böhme, G.A., Bon, C., Stutzmann, J.M., Doble, A., and Blanchard, J.C. (1991). Possible involvement of nitric oxide in long-term potentiation. Eur. J. Pharmacol. 199:379–381.
Boulton, C.L., Southam, E., and Garthwaite, J. (1995). Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase. Neuroscience 69:699–703.
Chetkovich, D.M., Klann, E., and Sweatt, J.D. (1993). Nitric oxide synthase-independent long-term potentiation in area CA1 of hippocampus. NeuroReport 4:919–922.
Corbin, J.D., Turko, I.V., Beasley, A., and Francis, S.H. (2000). Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur. J. Biochem. 267:2760–2767.
Doyle, C., Hölscher, C., Rowan, M.J., and Anwyl, R. (1996). The selective neuronal NO synthase inhibitor 7-nitroindazole blocks both long-term potentiation and depotentiation of field EPSPs in rat hippocampal CA1 in vivo. J. Neurosci. 16:418–424.
Felipo, V., and Butterworth, R.F. (2002). Neurobiology of ammonia. Prog. Neurobiol. 67:259–279.
Hawkins, R.D. (1996). NO honey, I don't remember. Neuron 16:465–467.
Hermenegildo, C., Montoliu, C., Llansola, M., Muñoz, M.D., Gaztelu, J.M., Miñana, M.D., and Felipo, V. (1998). Chronic hyperammonemia impairs the glutamate-nitricoxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur. J. Neurosci. 10:3201–3209.
Hu, G.Y., Hvalby, O., Walaas, S.I., Albert, K.A., Skjeflo, P., Andersen, P., and Greengard, P. (1987). Protein kinase C injection into hippocampal pyramidal cells elicits features of long term potentiation. Nature 328:426–429.
Lombardi, G., Mannaioni, P., Leonardi, P., Cherici, G., Carlà, V., and Moroni, F. (1994). Ammonium acetate inhibits ionotropic receptors and differentially affects metabotropic receptors for glutamate. J. Neural Transm. Gen. Sect. 97:187–196.
Louis, J.C., Revel, M.O., and Zwiller, J. (1993). Activation of soluble guanylate cyclase through phosphorylation by protein kinase C in intact PC12 cells. Biochim. Biophys. Acta 1177: 299–306.
Lovinger, D.M., Wong, K.L., Murakami, K., and Routtenberg, A. (1987). Protein kinase C inhibitors eliminate hippocampal long-term potentiation. Brain Res. 436:177–183.
Lu, Y., Kandel, E.R., and Hawkins, R.D. (1999). Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J. Neurosci. 19: 10250–10261.
Marcaida, G., Miñana, M.D., Burgal, M., Grisolia, S., and Felipo, V.(1995). Ammonia prevents activation of NMDA receptors by glutamate in rat cerebellar neuronal cultures Eur. J. Neurosci. 7:2389–2396.
Michalak, A., Knecht, K., and Butterworth, R.F. (1997). Hepatic encephalopathy in acute liver failure: role of the glutamate system. Adv. Exp. Med. Biol. 420:35–44.
Miñana, M.D., Llansola, M., Hermenegildo, C., Cucarella, C., Montoliu, C., Grisolía, S., and Felipo, V. (1997). Glutamate and muscarinic receptors in the molecular mechanism of acute ammonia toxicity and of its prevention. Adv. Exp. Med. Biol. 420:45–56.
Monfort, P., Muñoz, D., and Felipo, V. (2004). Hyperammonemia impairs long-term potentiation in hippocampus by alterating the modulation of cGMP-degrading phosphodiesterase by protein kinase G. Neurobiol. Dis. 15:1–10.
Monfort, P., Muñoz, D., Kosenko, E., and Felipo, V. (2002). Long- Term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. J. Neurosci. 22:10116–10122.
Moroni, F., Lombardi, G., Moneti, G., and Cortesini, C. (1983). The release and neosynthesis of glutamic acid are increased in experimental models of hepatic encephalopathy. J. Neurochem. 40:850–854.
Muñoz, D., Monfort, P., and Felipo, V. (2000). Hyperammonemia impairs NMDA receptor-dependent long-term-potentiation in the CA1 of rat hippocampus in vitro. Neurochem. Res. 25:437–441.
O'Dell, T.J., Hawkins, R.D., Kandel, E.R., and Arancio, O. (1991). Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc. Natl. Acad. Sci. 88:11285–11289.
Schuman, E.M., and Madison, D.V. (1991). A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 254:503–1506.
Schuman, E.M., Meffert, M.K., Schulman, H., and Madison, D.V. (1994). An ADP-ribosyl transferase as a potential target for nitric oxide action in hippocampal long-term potentiation. Proc. Natl. Acad. Sci. 91:11958–11962.
Selig, D.K., Segal, M.R., Liao, D., Malenka, R., Malinow, R., Nicoll, R.A., and Lisman, J.E. (1996). Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus. Learn. Memory 3:42–48.
Thomas, M.K., Francis, S.H., and Corbin, J.D. (1990). Substrate- and kinase-directed regulation of phosphorylation of a cGMP-binding phosphodiesterase by cGMP. J. Biol. Chem. 265:14971–14978.
Wu, J., Wang, Y., Rowan, M.J., and Anwy, L.R. (1998). 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. J. Neurosci. 18:3589–3596.
Wyatt, T.A., Naftilan, A.J., Francis, S.H., and Corbin, J.D. (1998). ANF elicits phosphorylation of the cGMP phosphodiesterase in vascular smooth muscle cells. Am. J. Physiol. 274:448–455.
Zhuo, M., Hu, Y., Schultz, C., Kandel, E.R., and Hawkins, R.D. (1994). Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Nature 368:635–639.
Zwiller, J., Revel, M.O., and Basset, P. (1981). Evidence for phosphorylation of rat brain guanylate cyclase by cyclic-AMP-dependent protein kinase. Biochem. Biophys. Res. Commun. 101:1381–1387.
Zwiller, J., Revel, M.O., and Malviya, A.N. (1985). Protein kinase C catalyzes phosphorylation of guanylate cyclase in vitro. J. Biol. Chem. 260:1350–1353.
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Monfort, P., Muñoz, MD. & Felipo, V. Molecular Mechanisms of the Alterations in NMDA Receptor-Dependent Long-Term Potentiation in Hyperammonemia. Metab Brain Dis 20, 265–274 (2005). https://doi.org/10.1007/s11011-005-7905-5
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DOI: https://doi.org/10.1007/s11011-005-7905-5