Hyperammonemia impairs long-term potentiation in hippocampus by altering the modulation of cGMP-degrading phosphodiesterase by protein kinase G.
Hyperammonemia impairs long-term potentiation (LTP) in hippocampus, by an unknown mechanism. LTP in hippocampal slices requires activation of the soluble guanylate cyclase (sGC)-protein kinase G (PKG)-cGMP-degrading phosphodiesterase pathway. The aim of this work was to assess whether hyperammonemia impairs LTP by impairing the tetanus-induced activation of this pathway. The tetanus induced a rapid cGMP rise, reaching a maximum at 10 s, both in the absence or presence of ammonia. The increase in cGMP is followed in control slices by a sustained decrease in cGMP due to PKG-mediated activation of cGMP-degrading phosphodiesterase, which is required for maintenance of LTP. Hyperammonemia prevents completely tetanus-induced cGMP decrease 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.
Monfort
Pilar
P
Laboratory of Neurobiology, Fundación Valenciana de Investigaciones Biomédicas, 46010 Valencia, Spain.
Muñoz
María-Dolores
MD
Felipo
Vicente
V
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000641:Ammonia / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation; D006162:Guanylate Cyclase; D006501:Hepatic Encephalopathy / Q000201:enzymology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D022124:Hyperammonemia / Q000201:enzymology* / Q000503:physiopathology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D018160:Receptors, Cytoplasmic and Nuclear; C016276:8-bromocyclic GMP; D000641:Ammonia; D017869:Cyclic GMP-Dependent Protein Kinases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP