Neurobiology of diseaseApr 21, 2015

Turning off adenosine A2A receptors may improve early working memory problems in Huntington's disease models

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Updated Apr 4, 2026

Abstract

Genetic inactivation of adenosine A(2A) receptors (A(2A)R) prevented working memory deficits in Huntington's disease mouse models at various developmental stages.

A(2A)R knockout mice demonstrated preserved working memory at post-natal week 6 and months 2 and 3 in R6/2-CAG120 and R6/2-CAG240 models, respectively.
The A(2A)R antagonist KW6002 reversed working memory deficits in R6/2-CAG240 mice at post-natal month 3.
Genetic inactivation of A(2A)R did not alter levels of ubiquitin-positive neuronal inclusions, astrogliosis, or a specific phosphorylation in the striatum.
A(2A)R blockade was associated with the control of long-term depression at cortico-striatal synapses in R6/2-CAG240 mice at post-natal week 6.
These findings suggest a potential role for A(2A)R in addressing cognitive deficits in Huntington's disease.

Simplified

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.

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Turning off adenosine A2A receptors may improve early working memory problems in Huntington's disease models

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