Format

Send to

Choose Destination
Neurobiol Dis. 2015 Feb;74:41-57. doi: 10.1016/j.nbd.2014.11.004. Epub 2014 Nov 11.

Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington's disease.

Author information

1
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.
2
CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal.
3
División de Neurociencias, Universidad Pablo de Olavide, 41013 Sevilla, Spain.
4
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.

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.

KEYWORDS:

Adenosine; Dopamine; Hippocampus; PKA pathway; R6/1 mice; Rotarod; Striatum; cAMP

PMID:
25449908
DOI:
10.1016/j.nbd.2014.11.004
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center