Norepinephrine Enhances a Discrete Form of Long-Term Depression during Fear Memory Storage
Norepinephrine Enhances a Discrete Form of Long-Term Depression during Fear Memory Storage
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DOI：
10.1523/jneurosci.3317-12.2013
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发表时间：
2013-07-17
影响因子：
5.3
通讯作者：
Huganir, Richard L.
中科院分区：
文献类型：
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作者：
Clem, Roger L.;Huganir, Richard L.
杏仁核兴奋性突触增强被认为是导致条件性恐惧和焦虑的原因之一。因此，行为灵活性的一个基础可能是这些通路被削弱，相应的情绪被削弱。然而，杏仁核依赖行为背景下的突触抑制仍然知之甚少。先前的工作发现杏仁外侧核(LA)钙通透性AMPA受体(CP-AMPAR)是长期抑郁症(LTD)和持续性恐惧减弱突触移除的关键靶点。在这里，我们证明了LA神经元表达两种同样有效的LTD，它们对蛋白激酶和磷酸酶活性的要求不同，对CP-AMPAR运输的影响也不同。选择性地从突触中移除CP-AMPAR依赖于第1组代谢性谷氨酸受体(MGluR1)和PKC信号，而不是另一种非选择性地移除AMPAR并需要钙调神经磷酸酶(PP2b)的LTD途径。有趣的是，这些形式的LTD之间的平衡在训练后通过激活恐惧条件下的小鼠的β-肾上腺素能受体而改变，导致mGluR依赖性抑郁的选择性增强。这些结果突显了LTD核心机制的复杂性，并表明去甲肾上腺素的暴露介导了一种形式的突触变塑性，重新校准了对记忆处理的恐惧。
Amygdala excitatory synaptic strengthening is thought to contribute to both conditioned fear and anxiety. Thus, one basis for behavioral flexibility could allow these pathways to be weakened and corresponding emotion to be attenuated. However, synaptic depression within the context of amygdala-dependent behavior remains poorly understood. Previous work identified lateral amygdala (LA) calcium-permeable AMPA receptors (CP-AMPARs) as a key target for synaptic removal in long-term depression (LTD) and persistent fear attenuation. Here we demonstrate that LA neurons express two equally potent forms of LTD with contrasting requirements for protein kinase and phosphatase activity and differential impact on CP-AMPAR trafficking. Selective removal of CP-AMPARs from synapses is contingent on group 1 metabotropic glutamate receptor (mGluR1) and PKC signaling, in contrast to an alternate LTD pathway that nonselectively removes AMPARs and requires calcineurin (PP2b). Intriguingly, the balance between these forms of LTD is shifted by posttraining activation of beta-adrenergic receptors in fear conditioned mice, resulting in selective augmentation of mGluR-dependent depression. These results highlight the complexity of core mechanisms in LTD and suggest that norepinephrine exposure mediates a form of synaptic metaplasticity that recalibrates fear memory processing.