title: Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease.
abstract: Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. However, the molecular events involved in this cognitive decline are still poorly understood. Here, using three different paradigms, the novel object recognition test, the T-maze spontaneous alternation task and the Morris water maze, we detected severe cognitive deficits in the R6/1 mouse model of HD before the onset of motor symptoms. When we examined the putative molecular pathways involved in these alterations, we observed hippocampal cAMP-dependent protein kinase (PKA) hyper-activation in naïve R6/1 mice compared with wild-type (WT) mice, whereas extracellular signal-regulated kinase 1/2 and calcineurin activities were not modified. Increased PKA activity resulted in hyper-phosphorylation of its substrates N-methyl-D-aspartate receptor subunit 1, Ras-guanine nucleotide releasing factor-1 and striatal-enriched protein tyrosine phosphatase, but not cAMP-responsive element binding protein or the microtubule-associated protein tau. In correlation with the over-activation of the PKA pathway, we found a down-regulation of the protein levels of some phosphodiesterase (PDE) 4 family members. Similar molecular changes were found in the hippocampus of R6/2 mice and HD patients. Furthermore, chronic treatment of WT mice with the PDE4 inhibitor rolipram up-regulated PKA activity, and induced learning and memory deficits similar to those seen in R6 mice, but had no effect on R6/1 mice cognitive impairment. Importantly, hippocampal PKA inhibition by infusion of Rp-cAMPS restored long-term memory in R6/2 mice. Thus, our results suggest that occlusion of PKA-dependent processes is one of the molecular mechanisms underlying cognitive decline in R6 animals.
authors.affiliation: Departament de Biologia Cel.lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Ana
authors.initials: A
authors.lastname: Saavedra
authors.forename: Olga
authors.initials: O
authors.lastname: Carretón
authors.forename: Xavier
authors.initials: X
authors.lastname: Xifró
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006816:Huntington Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D015203:Reproducibility of Results; D020889:Rolipram / Q000008:administration & dosage / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D020033:Protein Isoforms; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019703:Calcineurin; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram