Facilitation of Extinction Learning for Contextual Fear Memory by PEPA: A Potentiator of AMPA Receptors
Facilitation of Extinction Learning for Contextual Fear Memory by PEPA: A Potentiator of AMPA Receptors
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DOI：
10.1523/jneurosci.3842-06.2007
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发表时间：
2007-01
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通讯作者：
K. Zushida;Mikako Sakurai;K. Wada;M. Sekiguchi
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作者：
K. Zushida;Mikako Sakurai;K. Wada;M. Sekiguchi
背景恐惧记忆通过小鼠再次暴露于没有厌恶刺激的背景而减弱。这种现象被称为灭绝。在这里，我们报告的AMPA受体，4-[2-（苯磺酰氨基）乙硫基]-2，6-二氟苯氧基乙酰胺（PEPA）的增效剂，有力地促进小鼠的消退学习。将C57 BL/6 J小鼠暴露于新环境并通过电足电击刺激。在24 h（消退训练）和72 h（消退试验）后，将小鼠反复暴露于无足电击的环境中，并测量其冻结反应的持续时间。消退试验中的冻结反应持续时间始终短于消退训练中的值。与注射溶剂的对照组相比，在消退训练前15 min腹膜内注射PEPA显著减少了消退训练和测试期间的冻结反应的持续时间。PEPA的这种消退作用呈剂量依赖性，并可被AMPA受体拮抗剂NBQX（1，2，3，4-tetrahydro-6-硝基-2，3-dioxo-benzo[f]quinoxaline-7-sulfonamide）抑制。PEPA对恐惧记忆本身的获得和巩固没有影响。电生理研究表明，PEPA激活内侧前额叶皮层（mPFC）的神经网络更有力地比在基底外侧杏仁核和海马CA 1区。定量PCR研究表明，PEPA偏好AMPA受体亚基（GluR 3和GluR 4）和剪接变体（flop）在mPFC中的显著表达。mPFC内注射PEPA比杏仁核内注射PEPA更有效地促进消退。这些结果表明，PEPA促进消退学习通过AMPA受体激活主要在mPFC。
Contextual fear memory is attenuated by the re-exposure of mice to the context without aversive stimulus. This phenomenon is called extinction. Here, we report that a potentiator of AMPA receptors, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (PEPA), potently facilitates extinction learning in mice. C57BL/6J mice were exposed to novel context and stimulated by electrical footshock. After 24 h (extinction training) and 72 h (extinction test), the mice were repeatedly exposed to the context without footshock and the duration of their freezing response was measured. The duration of freezing response in the extinction test was consistently shorter than the value in extinction training. Intraperitoneal injection of PEPA 15 min before extinction training remarkably reduced the duration of freezing responses during the extinction training and test, compared with the vehicle-injected control mice. This action of PEPA on extinction was dose-dependent and inhibited by NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide), an AMPA receptor antagonist. PEPA had no effect on acquisition and consolidation of fear memory itself. Electrophysiological studies suggested that PEPA activates the neural network much more potently in the medial prefrontal cortex (mPFC) than in the basolateral amygdala and hippocampal CA1 field. Quantitative PCR studies suggested the pronounced expression of PEPA-preferring AMPA receptor subunits (GluR3 and GluR4) and a splice variant (flop) in the mPFC. An intra-mPFC injection of PEPA facilitated the extinction much more potently than an intra-amygdala injection of PEPA did. These results suggest that PEPA facilitates extinction learning through AMPA receptor activation mainly in the mPFC.