Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain

Giménez-Llort, Lydia; Schiffmann, Serge N.; Shmidt, Tanja; Canela, Laia; Camón, Lluïsa; Wassholm, Monica; Canals, Meritxell; Terasmaa, Anton; Fernández-Teruel, Albert; Tobeña, Adolf; Popova, Elena; Ferré, Sergi; Agnati, Luigi F.; Ciruela, Francisco; Martı́nez, Emili; Scheel-Krüger, Jørgen; Lluı́s, Carmen; Franco, Rafael; Fuxé, Kjell; Bäder, Michael

doi:10.1016/j.nlm.2006.05.004

Cited by 110 publications

(79 citation statements)

References 68 publications

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“…An earlier transgenic study suggested that A 2A Rs in the cortex and the hippocampus modulate working memory (Gimenez-Llort et al 2007), which is consistent with A 2A R's welldocumented functional effects on neuronal plasticity at the cortico-striatal ) and the hippocampal mossy fiber-CA3 pathways and with the identification of cortical regions (e.g., prefrontal and parietal cortices), in particular as the key structures subserving effective working memory based on electrophysiology and imaging (GoldmanRakic 1995; Rowe et al 2000).…”

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

confidence: 61%

“…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). The selectivity of these findings is consistent with the view that striatal function is not critical to forming spatial representations as such (Packard and McGaugh 1992;McDonald et al 2008;Berke et al 2009).…”

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

confidence: 98%

“…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: 96%

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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: 61%

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

confidence: 98%

mentioning

confidence: 96%

See 1 more Smart Citation

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

Wei¹,

Singer²,

Coelho³

et al. 2011

Learn. Mem.

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Caffeine Adenosine Receptors and Cognitive Behaviorssupporting

confidence: 78%

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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“…This evidence is in line with a pharmacological study showing that the adenosine A 2 receptor agonist CGS21680 reduced the anxiogenic effect of theophylline in the LD box (Imaizumi et al, 1994). Surprisingly, however, A 2A receptor overexpression did not alter anxiety-like responses in the elevated plus maze (Gimenez-Llort et al, 2007). Pharmacological and genetic inhibition of the A 2A receptor has also revealed its role in the regulation of anxiety in disease states, by other neuromodulators, or by drugs of abuse.…”

Section: The A2a Receptormentioning

confidence: 99%

Adenosine Signaling in Anxiety

Ruby¹,

Adams²,

Mrazek³

et al. 2011

Anxiety Disorders

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Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain

Cited by 110 publications

References 68 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 Signaling in Anxiety

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Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain

Cited by 110 publications

References 68 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 Signaling in Anxiety

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