Preferential enhancement of working memory in mice lacking adenosine A2A receptors

Zhou, Sai-jun; Zhu, Mei-er; Shu, Dan; Du, Xun-ping; Song, Xinyu; Wang, Xiaotong; Zheng, Ran; Cai, Xiaohong; Chen, Jiang‐Fan; He, Jincai

doi:10.1016/j.brainres.2009.09.082

Cited by 74 publications

(53 citation statements)

References 56 publications

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“…In contrast, spatial recognition memory and reference memory acquisition were largely unaffected by A 2A R inactivation in either knockout line. This pattern of outcomes closely resembles that seen following global A 2A R inactivation in mice (Zhou et al 2009), which also selectively enhanced working memory without affecting reference memory learning. Conversely, overexpression of A 2A Rs in the brain impaired working memory performance, but also did not affect reference memory function in transgenic rats (Gimenez-Llort et al 2007).…”

Section: Selective Inactivation Of Striatal Neuronal a 2a Rs Is Suffisupporting

confidence: 71%

“…Hence, A 2A Rs are uniquely positioned to fine-tune, at the circuitry level, the complex integration of dopaminergic, glutamatergic, and other neuronal signals that underlie cognitive processes including learning and memory. In transgenic models, A 2A R overexpression impaired short-term object recognition memory and working memory (Gimenez-Llort et al 2007), whereas A 2A R inactivation enhanced spatial recognition memory (Wang et al 2006) and working memory (Zhou et al 2009). The latter might suggest that suppression of A 2A R activity could be pro-cognitive as A 2A R inactivation also counteracted age-related and pathologic memory loss in rodents (Prediger et al 2005a,b,c;Dall'Igna et al 2007).…”

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confidence: 97%

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

Wei¹,

Singer²,

Coelho³

et al. 2011

Learn. Mem.

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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.

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Section: Selective Inactivation Of Striatal Neuronal a 2a Rs Is Suffisupporting

confidence: 71%

mentioning

confidence: 97%

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

Wei¹,

Singer²,

Coelho³

et al. 2011

Learn. Mem.

Self Cite

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“…Consistent with pharmacological studies [54], transgenic over-expression of the A 2A R in forebrain impair working memory in Morris water maze test, without affecting reference memory [55]. In keeping with this notion,we recently showed that A 2A R KO mice displayed selective enhancement in working memory in 8-arm radial maze and Morris water maze tests [56]. On the other hand, in contrast to the early pharmacological studies, A 1 R KO mice showed an intact spatial memory function [51,57].…”

Section: Caffeine Adenosine Receptors and Cognitive Behaviorssupporting

confidence: 74%

What Knock-Out Animals Tell Us About the Effects of Caffeine

Chen

Shen

et al. 2010

JAD

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Abstract.Caffeine is well known for its complex pharmacological actions, in part reflecting the multiple molecular targets of caffeine. The adenosine receptors are the primary extracellular targets of caffeine. Since caffeine has similar affinity for several adenosine receptors, it has been difficult to determine which receptor subtypes mediate caffeine's effects using pharmacological tools. The development of genetic mutant mice deficient in adenosine receptors and other signaling molecules has allowed targeted inquiry into the molecular targets by which caffeine elicits its biological effects on behavior and gene expression. This review summarizes recent work using genetic knockout models to elucidate the mechanisms of caffeine action in the brain. This review focuses on insights into caffeine action from genetic knockout models on: (1) the molecular basis for caffeine's effects on psychomotor activity; (2) the involvement of adenosine receptors in caffeine-mediated arousal and cognitive effects; and (3) a novel approach using knockout animals coupled with microarray profiling to validate multiple molecular targets of caffeine in striatal gene expression.

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“…To motivate performance in the T-maze test, animals were maintained on a food restriction regime as described elsewhere (56). First, the animals received daily habituation to the T-maze, the food rewards, and the experimenter (15 minutes per day) for 5 days.…”

Section: Methodsmentioning

confidence: 99%

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Shen¹,

Singer²,

Lytle³

et al. 2012

J. Clin. Invest.

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An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A 2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia. IntroductionDespite extensive research over half a century, schizophrenia remains a major health concern, affecting more than one percent of the population. Two hypotheses, those of dopaminergic hyperfunction (1) and glutamatergic hypofunction (2), are widely accepted conceptual frameworks for understanding the pathophysiology of schizophrenia and for the development of drugs for the treatment of either dopamine-related or glutamate-related symptoms of the disease (2, 3). This study addresses a third hypothesis, the "adenosine hypothesis of schizophrenia," which has recently been proposed as a novel concept to integrate the dopaminergic hyperfunction and glutamatergic hypofunction hypotheses (4).The purine ribonucleoside adenosine modulates neurotransmission through activation of 4 types of G protein-coupled adenosine receptors (ARs), A 1 R, A 2A R, A 2B R, and A 3 R, which exert spatially distinct functions within the brain on presynaptic and postsynaptic sites (5, 6). Presynaptically, adenosine regulates the release of both dopamine and glutamate (7,8), whereas the output of dopaminergic and glutamatergic neurotransmission is regulated by heterodimerization of ARs with dopamine and glutamate receptors (9, 10). Through these mechanisms adenosine exerts upstream control over both dopaminergic and glutamatergic signaling. Consequently, any disruption in adenosine homeostasis is expected to affect those 2 transmitter systems, which play fundamental roles in the pathophysiology of schizophrenia. This regulatory function of adenosine might provide a missing link for the functional integration of the dopamine and glutamate hypotheses. Conventional antipsychotic

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Preferential enhancement of working memory in mice lacking adenosine A2A receptors

Cited by 74 publications

References 56 publications

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

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

What Knock-Out Animals Tell Us About the Effects of Caffeine

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

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Preferential enhancement of working memory in mice lacking adenosine A2A receptors

Cited by 74 publications

References 56 publications

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

What Knock-Out Animals Tell Us About the Effects of Caffeine

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Contact Info

Product

Resources

About

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

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