title: In vivo administration of extracellular cGMP normalizes TNF-α and membrane expression of AMPA receptors in hippocampus and spatial reference memory but not IL-1β, NMDA receptors in membrane and working memory in hyperammonemic rats.
abstract: Patients with hepatic encephalopathy (HE) show working memory and visuo-spatial orientation deficits. Hyperammonemia is a main contributor to cognitive impairment in HE. Hyperammonemic rats show impaired spatial learning and learning ability in the Y maze. Intracerebral administration of extracellular cGMP restores learning in the Y-maze. The underlying mechanisms remain unknown. It also remains unknown whether extracellular cGMP improves neuroinflammation or restores spatial learning in hyperammonemic rats and if it affects differently reference and working memory. The aims of this work were: Spatial working and reference memory were assessed using the radial and Morris water mazes and neuroinflammation by immunohistochemistry and Western blot. Membrane expression of NMDA and AMPA receptor subunits was analyzed using the BS3 crosslinker. Extracellular cGMP was administered intracerebrally using osmotic minipumps. Chronic hyperammonemia induces neuroinflammation in hippocampus, with astrocytes activation and increased IL-1β, which are associated with increased NMDA receptors membrane expression and impaired working memory. This process is not affected by extracellular cGMP. Hyperammonemia also activates microglia and increases TNF-α, alters membrane expression of AMPA receptor subunits (increased GluA1 and reduced GluA2) and impairs reference memory. All these changes are reversed by extracellular cGMP. These results show that extracellular cGMP modulates spatial reference memory but not working memory. This would be mediated by modulation of TNF-α levels and of membrane expression of GluA1 and GluA2 subunits of AMPA receptors.
authors.affiliation: Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cabrera-Pastor
authors.affiliation: Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Hernandez-Rabaza
authors.affiliation: Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
authors.forename: Lucas
authors.initials: L
authors.lastname: Taoro-Gonzalez
authors.affiliation: Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Balzano
authors.affiliation: Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Llansola
authors.affiliation: Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain. Electronic address: vfelipo@cipf.es.
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D006152:Cyclic GMP / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D022124:Hyperammonemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism*
chemical_list: C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D006152:Cyclic GMP
keywords: AMPA receptors; Extracellular cGMP; IL-1β; Membrane expression; NMDA receptors; Neuroinflammation; Reference memory; Spatial learning; TNF-α; Working memory