Background Stimulation of dopamine D1 receptor (D1R) and adenosine A2Areceptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. Increased PKA activity contributes to hippocampal-dependent cognitive impairment in R6 mouse models of Huntington’s disease (HD), whereas D1R and A2AR signalling is known to be increased in the striatum.
Aims To analyse whether mutant huntingtin amplifies D1R and/or A2AR signalling in the hippocampus and the impact of their blockade on cognitive and motor dysfunction.
Methods/techniques D1R and A2AR functional efficiency and density were analysed by ELISA and binding assays in hippocampal nerve terminals. Mice were chronically injected with D1R and A2AR antagonists (SCH23390 and SCH58261, respectively). Cognitive function was assessed by the novel object recognition, T-maze spontaneous alternation and passive avoidance tests, and motor function by rotarod test. PKA activity was assessed by western blot against phospho-PKA catalytic subunit and phospho-PKA substrates.
Results We found that D1R and A2AR density and functional efficiency were increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signalling. In this line, chronic, but not acute, combined treatment with SCH23390 plus SCH58261 normalised PKA activity in the hippocampus, ameliorated hippocampal-dependent cognitive deficits and facilitated long-term potentiation in behaving R6/1 mice. In contrast, chronic treatment with D1R plus A2AR antagonist normalised striatal PKA activity, but did not improve motor deficits in R6/1 mice.
Conclusions Parallel alterations in dopaminergic and adenosinergic signalling in the hippocampus contribute to increased PKA activity and to hippocampal-dependent cognitive deficits, but not to motor dysfunction in HD. Targeting D1R and A2AR might be a novel therapeutic strategy to manage early cognitive impairment in HD.
Funding This work was supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI10/01072 to E. Perez-Navarro, and RETICS: RD06/0010/0006), Ministerio de Economia y Competitividad, Spain (BFU2011–29286 to A. Gruart, BFU2011–29089 to J. M. Delgado-García and SAF2011–29507 to J. Alberch), Generalitat de Catalunya, Spain (2009SGR-00326 to J. Alberch), Junta de Andalucía, Spain (BIO122 and CVI7222 to J.M. Delgado-García and A. Gruart), DARPA (09–68-ESR-FP-010 to R.A. Cunha), and FCT (PTDC/SAU-TOX/122005/2010 to R.A. Cunha). S. Tyebji is a fellow of Generalitat de Catalunya (AGAUR ST06914) and A. Saavedra was supported by Ministerio de Economia y Competitividad, Juan de la Cierva subprograme, Spain (JCI-2010-08207).
- R6/1 mice
- LTP in vivo