Protein Profiles Associated With Context Fear Conditioning and Their Modulation by Memantine
Protein Profiles Associated With Context Fear Conditioning and Their Modulation by Memantine
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DOI：
10.1074/mcp.m113.035568
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发表时间：
2014-04-01
影响因子：
7
通讯作者：
Gardiner, Katheleen J.
中科院分区：
文献类型：
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作者：
Ahmed, Md. Mahiuddin;Dhanasekaran, A. Ranjitha;Gardiner, Katheleen J.
对学习和记忆的分子基础的分析揭示了许多基因及其编码的蛋白质所发挥的作用的细节。由于大多数个体研究集中于少数蛋白质，因此蛋白质之间的关系及其对刺激的动态反应的许多复杂性尚不清楚。我们使用反相蛋白阵列 (RPPA) 技术来评估接受情境恐惧调节 (CFC) 训练的小鼠海马和皮层亚细胞部分中 80 多种蛋白质/蛋白质修饰的水平。蛋白质包括信号通路的成分、一些由早期基因编码或参与细胞凋亡和炎症的成分，以及谷氨酸受体的亚基。训练后一小时，超过一半的蛋白质水平在一个或多个部分发生了变化，其中包括丝裂原激活蛋白激酶的多种成分、MAPK、雷帕霉素的机械靶标、MTOR、通路、谷氨酸受体亚基和 NOTCH 通路调节剂、NUMB 同源物（果蝇）。仅海马核部分就有 37 种蛋白质的水平发生变化。据报道，阿尔茨海默病患者大脑中的 13 种蛋白质分析水平出现异常。因此，我们进一步研究了用美金刚（一种被批准用于治疗 AD 的药物）治疗的小鼠的蛋白质谱。在海马体中，单独使用美金刚会引起许多与 CFC 后观察到的变化类似的变化，并改变与阿尔茨海默病异常相关的七种蛋白质的水平。最后，为了进一步探索这些数据集的相关性，我们将对 CFC 和美金刚的反应叠加到长期增强途径的组成部分上，这是一个促进学习和记忆形成的过程。长时程增强途径的 14 个成分和 26 个与成分相互作用的蛋白质对 CFC 和/或美金刚有反应。这些数据集共同提供了正常学习后蛋白质反应和相互作用的多样性和复杂性的新视角。
Analysis of the molecular basis of learning and memory has revealed details of the roles played by many genes and the proteins they encode. Because most individual studies focus on a small number of proteins, many complexities of the relationships among proteins and their dynamic responses to stimulation are not known. We have used the technique of reverse phase protein arrays (RPPA) to assess the levels of more than 80 proteins/protein modifications in subcellular fractions from hippocampus and cortex of mice trained in Context Fear Conditioning (CFC). Proteins include components of signaling pathways, several encoded by immediate early genes or involved in apoptosis and inflammation, and subunits of glutamate receptors. At one hour after training, levels of more than half the proteins had changed in one or more fractions, among them multiple components of the Mitogen-activated protein kinase, MAPK, and Mechanistic Target of Rapamycin, MTOR, pathways, subunits of glutamate receptors, and the NOTCH pathway modulator, NUMB homolog (Drosophila). Levels of 37 proteins changed in the nuclear fraction of hippocampus alone. Abnormalities in levels of thirteen proteins analyzed have been reported in brains of patients with Alzheimer's Disease. We therefore further investigated the protein profiles of mice treated with memantine, a drug approved for treatment of AD. In hippocampus, memantine alone induced many changes similar to those seen after CFC and altered the levels of seven proteins associated with Alzheimer's Disease abnormalities. Lastly, to further explore the relevance of these datasets, we superimposed responses to CFC and memantine onto components of the long term potentiation pathway, a process subserving learning and memory formation. Fourteen components of the long term potentiation pathway and 26 proteins interacting with components responded to CFC and/or memantine. Together, these datasets provide a novel view of the diversity and complexity in protein responses and interactions following normal learning.