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

Abstract 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 A 2A 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.