TrkB Modulates Fear Learning and Amygdalar Synaptic Plasticity by Specific Docking Sites
TrkB Modulates Fear Learning and Amygdalar Synaptic Plasticity by Specific Docking Sites
复制标题
DOI：
10.1523/jneurosci.1707-09.2009
复制
发表时间：
2009-08-12
影响因子：
5.3
通讯作者：
Minichiello, Liliana
中科院分区：
文献类型：
--
作者：
Musumeci, Gabriele;Sciarretta, Carla;Minichiello, Liliana
了解恐惧神经回路的调节显然是神经生物学最重要的目标之一。响应外部刺激的蛋白质磷酸化被认为是神经回路动态变化的主要机制。 TrkB (Ntrk2) 神经营养蛋白受体酪氨酸激酶主要通过两个磷酸化位点 [Y515/Shc 位点；Y515/Shc 位点； Y816/PLC γ（磷脂酶 C γ）位点]。为了确定恐惧学习和 TrkB 下游杏仁核突触可塑性所需的分子途径，我们使用在这两个位点（Y515F 或 Y816F）之一携带单点突变的高度定义的遗传小鼠模型来检查通过这些位点激活的途径与巴甫洛夫恐惧调节（FC）的生理相关性，以及通过现场记录测量的突触可塑性 不同杏仁核的神经元。我们发现 Y816F 点突变会损害 FC 的获得、杏仁核突触可塑性和突触处的 CaMKII 信号传导。相比之下，Y515F 点突变会影响巩固，但不会影响 FC 的获得，还会改变 AKT 信号传导。因此，TrkB 受体通过两个主要的磷酸化对接位点调节恐惧学习和杏仁核突触可塑性的特定阶段。
Understanding the modulation of the neural circuitry of fear is clearly one of the most important aims in neurobiology. Protein phosphorylation in response to external stimuli is considered a major mechanism underlying dynamic changes in neural circuitry. TrkB (Ntrk2) neurotrophin receptor tyrosine kinase potently modulates synaptic plasticity and activates signal transduction pathways mainly through two phosphorylation sites [Y515/Shc site; Y816/PLC gamma (phospholipase C gamma) site]. To identify the molecular pathways required for fear learning and amygdalar synaptic plasticity downstream of TrkB, we used highly defined genetic mouse models carrying single point mutations at one of these two sites (Y515F or Y816F) to examine the physiological relevance of pathways activated through these sites for pavlovian fear conditioning (FC), as well as for synaptic plasticity as measured by field recordings obtained from neurons of different amygdala nuclei. We show that a Y816F point mutation impairs acquisition of FC, amygdalar synaptic plasticity, and CaMKII signaling at synapses. In contrast, a Y515F point mutation affects consolidation but not acquisition of FC to tone, and also alters AKT signaling. Thus, TrkB receptors modulate specific phases of fear learning and amygdalar synaptic plasticity through two main phosphorylation docking sites.