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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists / pharmacology
  • Animals
  • Benzazepines / pharmacology
  • Cognition Disorders / etiology
  • Cognition Disorders / physiopathology*
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiopathology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Dopamine Antagonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • Huntington Disease / complications
  • Huntington Disease / physiopathology*
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Pyrimidines / pharmacology
  • Receptor, Adenosine A2A / metabolism*
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / metabolism*
  • Triazoles / pharmacology

Substances

  • 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
  • Adenosine A2 Receptor Antagonists
  • Benzazepines
  • Dopamine Antagonists
  • Pyrimidines
  • Receptor, Adenosine A2A
  • Receptors, Dopamine D1
  • SCH 23390
  • Triazoles
  • Cyclic AMP-Dependent Protein Kinases