Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

Abstract

The adenosine A 2A receptor (A 2A R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A 2A R inactivation can be pro-cognitive, analyses of A 2A R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A 2A Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A 2A Rs. Specifically, we evaluated the cognitive impacts of conditional A 2A R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A 2A R KO) or to striatum alone (st-A 2A R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A 2A R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A 2A Rs as they were captured by A 2A R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D 1 , D 2 , or A 1 receptor expression was found. This study provides the first direct demonstration that targeting striatal A 2A Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

Superior working memory and behavioural habituation but diminished psychomotor coordination in mice lacking the ecto-5′-nucleotidase (CD73) gene

“…A2R antagonism has been shown to block memory deficits induced by beta-amyloid peptides [31]. Similarly, A2aR KO mice showed enhanced working memory in the water maze and the radial maze tasks [32] and the genetic deletion of A2aR in the forebrain or striatum improved spatial working memory [33]. The selective enhancement of spatial working memory in A2aR deficient mice is in line with the improved spatial working memory performance of CD73−/− mice described in the present report.…”

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

“…with the working memory enhancement seen following genetic inactivation of A 2A R (48). However, the latter was mainly attributed to the loss of striatal A 2A Rs (48) and likely reflects a regionspecific mechanism at the subcortical level rather than an effect on the neural processes underlying learning and memory in the cortex and/or hippocampus.…”

“…However, the latter was mainly attributed to the loss of striatal A 2A Rs (48) and likely reflects a regionspecific mechanism at the subcortical level rather than an effect on the neural processes underlying learning and memory in the cortex and/or hippocampus. One might therefore speculate that hippocampal LTP would be negatively affected in the presence of reduced adenosine tone, leading in turn to impaired working memory performance in adenosine-deficient Adk-tg mice.…”

Adenosine A2A Receptor Deficiency Alleviates Blast-Induced Cognitive Dysfunction

“…12 The platform was made 'visible' by a local cue place directly above the escape platform and was varied between the 2 days. This served to familiarize the mice with the apparatus and procedure, to allow them to acquire the necessary escape response, and to screen out those mice that had trouble in swimming or escape behavior.…”

“…11,12 The test consisted of three parts: visible cue task, reference memory task, and working memory task. The same cohorts of mice were tested for both reference memory and working memory in each test period (1, 4, or 8 weeks).…”