Stress and glucocorticoids impair memory retrieval via β2-adrenergic, Gi/o-coupled suppression of cAMP signaling.
Stress and glucocorticoids impair memory retrieval via β2-adrenergic, Gi/o-coupled suppression of cAMP signaling.
复制标题
DOI：
10.1523/jneurosci.2122-11.2011
复制
发表时间：
2011-10-05
期刊：
影响因子：
--
通讯作者：
Thomas SA
中科院分区：
文献类型：
--
作者：
Schutsky K;Ouyang M;Castelino CB;Zhang L;Thomas SA
急性应激损害海马依赖性记忆的恢复，这种作用被外源性应激反应性糖皮质激素所模拟。已经提出糖皮质激素通过促进去甲肾上腺素（NE）（一种应激反应性神经递质）的释放和/或阻断其再摄取来影响记忆。也有人提出，这种增强的NE信号传导通过刺激β1-肾上腺素能受体和升高cAMP水平而损害记忆提取。相反，其他证据表明，NE，β1和cAMP信号转导是短暂需要的恢复海马依赖性记忆。为了解决这一差异，在测试抑制性回避或恐惧条件反射的记忆之前，对具有和不具有基因靶向突变的野生型大鼠和小鼠进行应激或用糖皮质激素和/或肾上腺素能受体药物治疗。在这里，我们报告糖皮质激素不需要NE损害检索。然而，应激和糖皮质激素诱导的提取障碍依赖于β2（而不是β1）-肾上腺素能受体的激活。为这两种受体的相反功能提供解释，应激、糖皮质激素和β2激动剂对恢复的损害作用被百日咳毒素阻断，百日咳毒素使Gi/o偶联受体的信号传导失活。在海马脑片中，β2信号降低cAMP水平，并大大减少β1信号介导的cAMP增加。最后，增加海马中的cAMP信号传导防止了系统性β2激动剂或糖皮质激素对恢复的损害。这些结果表明，β2受体可能是急性应激的关键效应器，并且β1和β2受体在CNS信号传导和认知中具有相当不同的作用。
Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating β1-adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, β1 and cAMP signaling are transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs prior to testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of β2 (but not β1)-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and β2 agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by Gi/o-coupled receptors. In hippocampal slices, β2 signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by β1 signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic β2 agonists or glucocorticoids. These results demonstrate that the β2 receptor can be a critical effector of acute stress, and that β1 and β2 receptors can have quite distinct roles in CNS signaling and cognition.