Chronic hyperammonemia in vivo impairs long-term potentiation in hippocampus by altering activation of cyclic GMP-dependent-protein kinase and of phosphodiesterase 5.
Long-term potentiation (LTP) is impaired in the CA1 area of hippocampal slices from rats with chronic moderate hyperammonemia. We studied the mechanisms by which hyperammonemia in vivo impairs LTP. This process requires sequential activation of soluble guanylate cyclase, cyclic GMP-dependent protein kinase (PKG) and cyclic GMP-degrading phosphodiesterase. Application of the tetanus induced a rapid increase of cyclic GMP in slices from control or hyperammonemic rats, which is followed in control slices by a sustained decrease in cyclic GMP due to sustained activation of cyclic GMP-degrading phosphodiesterase, which in turn is due to sustained activation of PKG. In slices from rats with chronic hyperammonemia tetanus-induced decrease in cyclic GMP was delayed and transient due to lower and transient activation of PKG and of the phosphodiesterase. Hyperammonemia-induced impairment of LTP may be involved in the alterations of cognitive function in patients with hepatic encephalopathy.
Monfort
Pilar
P
Laboratory of Neurobiology, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.
Muñoz
María-Dolores
MD
Felipo
Vicente
V
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004558:Electric Stimulation; D004789:Enzyme Activation; D006624:Hippocampus / Q000503:physiopathology*; D022124:Hyperammonemia / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP