1] School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea. [2].
Nat Neurosci. 2013 Oct;16(10):1436-44. doi: 10.1038/nn.3491. Epub 2013 Aug 25.
Fear renewal, a widely pursued model of post-traumatic stress disorder and phobias, refers to the context-specific relapse of conditioned fear after extinction. However, its molecular mechanisms are largely unknown. We found that renewal-inducing stimuli, generally believed to be insufficient to induce synaptic plasticity, enhanced excitatory synaptic strength, activity of synaptic GluA2-lacking AMPA receptors and Ser831 phosphorylation of synaptic surface GluA1 in the lateral nucleus of the amygdala (LAn) of fear-extinguished rats. Consistently, the induction threshold for LAn synaptic potentiation was considerably lowered after extinction, and renewal occluded this low-threshold potentiation. The low-threshold potentiation (a potential cellular substrate for renewal), but not long-term potentiation, was attenuated by dialysis into LAn neurons of a GluA1-derived peptide that competes with Ser831-phosphorylated GluA1. Microinjections of the same peptide into the LAn attenuated fear renewal, but not fear learning. Our findings suggest that GluA1 phosphorylation constitutes a promising target for clinical treatment of aberrant fear-related disorders.
恐惧再现是一种广泛研究的创伤后应激障碍和恐惧症模型，指的是在消退后条件性恐惧的特定情境下复发。然而，其分子机制在很大程度上是未知的。我们发现，通常被认为不足以诱导突触可塑性的再现诱导刺激增强了恐惧消退大鼠杏仁外侧核（LAn）中的兴奋性突触强度、突触 GluA2 缺失型 AMPA 受体活性和突触表面 GluA1 的 Ser831 磷酸化。一致地，LAn 突触增强的诱导阈值在消退后显著降低，而再现阻止了这种低阈值增强。低阈值增强（再现的潜在细胞基础），而不是长时程增强，被注入 LAn 神经元的与 Ser831 磷酸化的 GluA1 竞争的 GluA1 衍生肽减弱。将相同的肽注入 LAn 会减弱恐惧再现，但不会减弱恐惧学习。我们的发现表明，GluA1 磷酸化是治疗异常恐惧相关障碍的有前途的靶点。
