M16 D1R and A2AR Blockade Normalises PKA Activity and Improves Hippocampal-dependent Cognitive Dysfunction but not Motor Deficits in Huntington's Disease. (17th September 2014)

• Record Type: Journal Article
• Authors: Saavedra, A; Tyebji, S; Canas, PM; Pliassova, A; Delgado-García, JM; Alberch, J; Cunha, RA; Gruart, A; Pérez-Navarro, E
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 85(2014)Supplement 1
• Page Start: A99
• Page End: A100
• Publication Date: 2014-09-17
• Subjects: R6/1 mice -- LTP in vivo -- SCH23390 -- SCH58261; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2014-309032.288
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2A R) 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 A2A R signalling is known to be increased in the striatum. Aims: To analyse whether mutant huntingtin amplifies D1R and/or A2A R signalling in the hippocampus and the impact of their blockade on cognitive and motor dysfunction. Methods/techniques: D1R and A2A R functional efficiency and density were analysed by ELISA and binding assays in hippocampal nerve terminals. Mice were chronically injected with D1R and A2A R 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 A2A R 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 A2A R 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 A2A R 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).