The slow afterhyperpolarization: a target of β1-adrenergic signaling in hippocampus-dependent memory retrieval.
The slow afterhyperpolarization: a target of β1-adrenergic signaling in hippocampus-dependent memory retrieval.
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DOI：
10.1523/jneurosci.3834-12.2013
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发表时间：
2013-03-13
期刊：
影响因子：
--
通讯作者：
Thomas SA
中科院分区：
文献类型：
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作者：
Zhang L;Ouyang M;Ganellin CR;Thomas SA
在啮齿类动物中，海马中去甲肾上腺素（NE）的肾上腺素能信号是中期记忆恢复所必需的。NE通过刺激β1-肾上腺素能受体、产生环AMP以及激活蛋白激酶A（PKA）和cAMP激活的交换蛋白来促进恢复。然而，这种信号通路的最终效应子尚未确定。在海马中肾上腺素能信号的众多靶点中，缓慢后超极化（sAHP）是一个有吸引力的候选者，因为其被β1信号降低增强兴奋性神经传递。在这里，我们报告说，减少sAHP是至关重要的便利检索NE。sAHP的直接阻断剂，以及激活sAHP的L型电压依赖性钙内流的阻断剂，在缺乏NE或β1受体的突变小鼠中挽救了恢复。与此互补的是，L型钙内流的促进剂损害野生型小鼠的检索。此外，我们还研究了NE在离体海马切片中观察到的与学习相关的sAHP降低中的作用。我们发现，这种减少sAHP依赖于诱导持久PKA活性，特别是在条件切片。有趣的是，这种持续的PKA活性是在切片制备过程中而不是在学习过程中由NE/β1信号转导诱导的。这些观察结果表明，在sAHP的减少可能不存在自主在体内，但可能是由神经调节输入，这是一致的想法，NE是需要在体内减少的sAHP在记忆检索。
In rodents, adrenergic signaling by norepinephrine (NE) in the hippocampus is required for the retrieval of intermediate-term memory. NE promotes retrieval via the stimulation of β1-adrenergic receptors, the production of cyclic AMP, and the activation of both protein kinase A (PKA) and the exchange protein activated by cAMP. However, a final effector for this signaling pathway has not been identified. Among the many targets of adrenergic signaling in the hippocampus, the slow afterhyperpolarization (sAHP) is an appealing candidate because its reduction by β1 signaling enhances excitatory neurotransmission. Here we report that reducing the sAHP is critical for the facilitation of retrieval by NE. Direct blockers of the sAHP, as well as blockers of the L-type voltage-dependent calcium influx that activates the sAHP, rescue retrieval in mutant mice lacking either NE or the β1 receptor. Complementary to this, a facilitator of L-type calcium influx impairs retrieval in wild-type mice. In addition, we examined the role of NE in the learning-related reduction of the sAHP observed ex vivo in hippocampal slices. We find that this reduction in the sAHP depends on the induction of persistent PKA activity specifically in conditioned slices. Interestingly, this persistent PKA activity is induced by NE/β1 signaling during slice preparation rather than during learning. These observations suggest that the reduction in the sAHP may not be present autonomously in vivo, but is likely induced by neuromodulatory input, which is consistent with the idea that NE is required in vivo for reduction of the sAHP during memory retrieval.