title: Extracellular cGMP Modulates Learning Biphasically by Modulating Glycine Receptors, CaMKII and Glutamate-Nitric Oxide-cGMP Pathway.
abstract: It has been proposed that extracellular cGMP modulates the ability to learn a Y maze task, but the underlying mechanisms remained unknown. Here we show that extracellular cGMP, at physiological concentrations, modulates learning in the Y maze in a biphasic way by modulating the glutamate-nitric oxide-cGMP pathway in cerebellum. Extracellular cGMP reduces glycine receptors activation inducing a voltage-dependent calcium-channels-mediated increase of calcium in Purkinje neurons. This calcium increase modulates CaMKII phosphorylation in a biphasic way. When basal calcium concentration is low extracellular cGMP reduces CaMKII phosphorylation, increasing nitric oxide synthase activity, the glutamate-NO-cGMP pathway function and learning ability. When basal calcium is normal extracellular cGMP increases CaMKII phosphorylation, reducing nitric oxide synthase activity, the pathway function and learning. These data unveil new mechanisms modulating learning in the Y maze and likely other learning types which may be therapeutic targets to improve learning in pathological situations associated with altered cGMP levels.
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: Michele
authors.initials: M
authors.lastname: Malaguarnera
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: Marta
authors.initials: M
authors.lastname: Llansola
authors.affiliation: Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D007858:Learning / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018009:Receptors, Glycine; D009569:Nitric Oxide; D018698:Glutamic Acid; D019001:Nitric Oxide Synthase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006152:Cyclic GMP; D002118:Calcium