title: Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington's disease.
abstract: Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease.
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Shiraz
authors.initials: S
authors.lastname: Tyebji
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Saavedra
authors.affiliation: CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Canas
authors.affiliation: CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Anna
authors.initials: A
authors.lastname: Pliassova
authors.affiliation: División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Delgado-García
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.affiliation: CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain.
authors.forename: Agnès
authors.initials: A
authors.lastname: Gruart
authors.affiliation: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. Electronic address: estherperez@ub.edu.
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006816:Huntington Disease / Q000150:complications / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D001552:Benzazepines; D018492:Dopamine Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D014230:Triazoles; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Adenosine; Dopamine; Hippocampus; PKA pathway; R6/1 mice; Rotarod; Striatum; cAMP