title: PDE10 inhibition increases GluA1 and CREB phosphorylation and improves spatial and recognition memories in a Huntington's disease mouse model.
abstract: Huntington's disease (HD) causes motor disturbances, preceded by cognitive impairment, in patients and mouse models. We showed that increased hippocampal cAMP-dependent protein kinase (PKA) signaling disrupts recognition and spatial memories in R6 HD mouse models. However, unchanged levels of hippocampal phosphorylated (p) cAMP-responsive element-binding protein (CREB) suggested unaltered nuclear PKA activity in R6 mice. Here, we extend this finding by showing that nuclear pPKA catalytic subunit (Thr197) and pPKA substrate levels were unaltered in the hippocampus of R6/1 mice. Phosphodiesterases (PDEs) play an important role in the regulation of PKA activity. PDE10A, a cAMP/cGMP dual-substrate PDE, was reported to be restricted to the nuclear region in nonstriatal neurons. Using cell fractionation we confirmed that PDE10A was enriched in nuclear fractions, both in wild-type and R6/1 mice hippocampus, without differences in its levels or intracellular distribution between genotypes. We next investigated whether inhibition of PDE10 with papaverine could improve cognitive function in HD mice. Papaverine treatment improved spatial and object recognition memories in R6/1 mice, and significantly increased pGluA1 and pCREB levels in R6/1 mice hippocampus. Papaverine likely acted through the activation of the PKA pathway as the phosphorylation level of distinct cGMP-dependent kinase (cGK) substrates was not modified in either genotype. Moreover, hippocampal cAMP, but not cGMP, levels were increased after acute papaverine injection. Our results show that inhibition of PDE10 improves cognition in R6 mice, at least in part through increased GluA1 and CREB phosphorylation. Thus, PDE10 might be a good therapeutic target to improve cognitive impairment in HD.
authors.affiliation: Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 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: Helena
authors.initials: H
authors.lastname: Arumí
authors.forename: Shiraz
authors.initials: S
authors.lastname: Tyebji
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006816:Huntington Disease / Q000150:complications / Q000235:genetics; D018782:Maze Learning; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010208:Papaverine / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D018091:Receptors, AMPA; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D013028:Space Perception / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D050882:CREB-Binding Protein; D010208:Papaverine; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D018091:Receptors, AMPA; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C492284:Pde10a protein, mouse
keywords: CRTC1; PKA pathway; cAMP; hippocampus; papaverine