A necessary role for GluR1 serine 831 phosphorylation in appetitive incentive learning
A necessary role for GluR1 serine 831 phosphorylation in appetitive incentive learning
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DOI：
10.1016/j.bbr.2008.03.026
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发表时间：
2008-08-22
影响因子：
2.7
通讯作者：
Huganir, Richard L.
中科院分区：
文献类型：
--
作者：
Crombag, Hans S.;Sutton, Jeffrey M.;Huganir, Richard L.
人们普遍认为，突触后AMPA受体的调节是学习和记忆基础的突触功效变化的关键组成部分。AMPA受体的调节通过受体的运输和/或受体通道特性的调节发生，并且这两个过程都依赖于受体的磷酸化。使用同源重组（敲入）技术，我们针对MPA-GluR 1受体上的两个磷酸化位点：CaMKII/PKC Ser 831位点和PKA Set 845位点。然后，对这些位点中的一个或两个突变的小鼠进行激励学习任务的测试，该任务评估了它们获得线索和奖励之间的简单关联的能力，然后使用该线索作为指导它们行为的标记（条件强化）。我们报告说，而野生型小鼠表现出增强响应奖励相关的线索，小鼠与磷酸化位点或集831位点单独突变，未能显示这样的条件强化效应。相比之下，只有Ser 845位点缺陷的小鼠表现出正常的CS+增强反应。因此，在丝氨酸831磷酸化位点的行动是必要的正常条件强化。最后，行为缺陷是高度特异性的：在许多其他动机表现的测量中，包括食物本身强化的反应，不受突变的影响。我们的研究结果为食欲激励学习的分子机制提供了新的证据，这种机制在调节正常的动机行为以及适应不良的形式（如成瘾和饮食失调）方面至关重要。(C)2008 Elsevier B. V.保留所有权利。
It is widely thought that regulation of post-synaptic AMPA receptors is a critical component in changes in synaptic efficacy underlying learning and memory. The regulation of AMPA receptors occurs through trafficking of the receptor and/or modulation of the receptor's channel properties and both of these processes depend on phosphorylation of the receptor. Using homologous recombination (knock-in) techniques we targeted two phosphorylation sites on the MPA-GluR1 receptor: the CaMKII/PKC Ser 831 site and the PKA Set 845 site. Mice with either or both of these sites mutated were then tested on an incentive learning task that assessed their ability to acquire a simple association between a cue and reward and to then use this cue as a reinforcer to guide their behavior (conditioned reinforcement). We report that, whereas WT mice showed enhanced responding for the reward-associated cue, mice with mutations of both phosphorylation sites or the Set 831 site alone, failed to show such a conditioned reinforcement effect. By contrast, mice with only the Ser 845 site deficient showed normal CS+ reinforced responding. Thus, action at the Ser 831 phosphorylation site was necessary for normal conditioned reinforcement. Finally, the behavioral deficit was highly specific: performance on a number of other measures of motivated performance, including responding reinforced by the food itself, was unaffected by the mutations. Our findings provide novel evidence for a molecular mechanism in a form of appetitive incentive learning critical in regulating normal motivated behavior, as well as maladaptive forms such as addiction and eating disorders. (C) 2008 Elsevier B.V. All rights reserved.