Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models

Neurobiol Dis. 2015 Jul;79:70-80. doi: 10.1016/j.nbd.2015.03.030. Epub 2015 Apr 16.


Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A(2A) receptors (A(2A)R), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A(2A)R inactivation to prevent cognitive deficits in early HD, we cross-bred A(2A)R knockout (KO) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2-CAG120-A(2A)R KO and R6/2-CAG240-A(2A)R KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A(2A)R prevented working memory deficits induced by R6/2-CAG120 at post-natal week 6 and by R6/2-CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A2(A)R antagonist KW6002 selectively reverted working memory deficits in R6/2-CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A(2A)R did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A(2A)R blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2-CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A(2A)R provides a proof-of-principle for A(2A)R as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation.

Keywords: Adenosine A(2A) receptor; Cognition; Huntington's disease; Long-term depression; R6/2 mice; Working memory.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine A2 Receptor Antagonists / pharmacology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / pathology
  • Astrocytes / physiology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Cognition Disorders / drug therapy
  • Cognition Disorders / pathology
  • Cognition Disorders / physiopathology
  • Corpus Striatum / drug effects
  • Corpus Striatum / pathology
  • Corpus Striatum / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Gliosis / pathology
  • Gliosis / physiopathology
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology*
  • Inclusion Bodies / pathology
  • Inclusion Bodies / physiology
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology
  • Male
  • Memory Disorders / drug therapy
  • Memory Disorders / pathology
  • Memory Disorders / physiopathology*
  • Memory, Short-Term / drug effects
  • Memory, Short-Term / physiology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Purines / pharmacology
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism*
  • Ubiquitin / metabolism


  • Adenosine A2 Receptor Antagonists
  • Purines
  • Receptor, Adenosine A2A
  • Ubiquitin
  • istradefylline