Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain
Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain
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DOI：
10.1016/j.nlm.2006.05.004
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发表时间：
2007-01-01
影响因子：
2.7
通讯作者：
Bader, Michael
中科院分区：
文献类型：
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作者：
Gimenez-Llort, Lydia;Schiffmann, Serge N.;Bader, Michael
尽管A（2A）受体（A(2A)R）亚型在学习和记忆中的具体作用尚不清楚，但中枢神经系统中的腺苷受体与不同行为模式和认知功能的调节有关。在本研究中，我们建立了一种新的转基因大鼠菌株TGR(NSEhA2A)，该菌株主要在大脑皮层、海马区和小脑中过表达腺苷a (2A)Rs。随后，我们探讨了A(2A)Rs过表达与学习记忆功能的相关性。我们对动物进行了一些学习和记忆任务（六臂径向隧道迷宫、t形迷宫、物体识别和几种Morris水迷宫范式）和其他自发运动活动（开放场地、六边形隧道迷宫）和焦虑（加迷宫）的行为评估，因为这些行为的改变可能会干扰认知功能的评估。A(2A)Rs的过表达不会改变运动表现和情绪/焦虑样行为。TGR（NSEhA(2A)）显示空间参考记忆的海马依赖学习正常。然而，他们提出了工作记忆缺陷，通过在6臂径向隧道迷宫的盲臂中持续错误的表现，减少对新物体的识别，以及在同一天进行的四次试验中缺乏学习改善，这在莫里斯水迷宫的重复习得范式中没有连续几天观察到。鉴于腺苷酸和多巴胺能功能之间的相互依赖关系，目前的研究结果表明，新型TGR（NSEhA(2A)）可作为精神分裂症或帕金森病患者工作记忆缺陷和认知中断相关的过度刺激皮质a (2A)Rs或多巴胺能前额功能障碍的动物模型。(c) 2006爱思唯尔公司版权所有。
Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA(2A)) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and doparninergic function, the present results render the novel TGR(NSEhA(2A)) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic preftontal dysfunction as seen in schizophrenic or Parkinson's disease patients. (c) 2006 Elsevier Inc. All rights reserved.