Novel roles by glutamatergic receptors in the synaptic effects of beta amyloid

描述(由申请人提供)：谷氨酸能受体在β-淀粉样长时程增强和抑制的突触效应中的新作用(LTP和LTD)是脊椎动物突触可塑性的有前途的和广泛研究的例子，在这些例子中，分别有持续的突触增强或减少，在突触活性的短暂调节期之后。在这两种形式的可塑性中，突触上的NMDA受体(-Rs)和AMPA受体(-Rs)发挥着关键和不同的作用。这项拨款的总体目标是研究控制LTP和LTD的亚细胞信号。最近，我们发现，β-淀粉样蛋白(A？)，一种与阿尔茨海默病密切相关的多肽，对AMPA-R转运有显著影响，需要一种新形式的NMDA-R信号。在此授权期内，我们将研究NMDA受体和AMPA受体及其相关蛋白在Aβ对突触的影响中所起的不同作用。我们的初步研究表明，需要一种非离子形式的NMDA-R信号以及特定的AMPA-R亚基来修饰兴奋性突触。在这里，我们将使用几种互补的方法来检验这些发现，包括分子生物学、电生理学和双光子激光扫描显微镜。这些研究将使用异源细胞系、器官型大鼠海马片和转基因小鼠。这些研究的结果将阐明阿尔茨海默病的机制，并提供潜在有效的治疗策略。具体目的是确定：特定目标1：NMDA受体及相关分子在A？诱导的突触抑制中所起的作用

DESCRIPTION (provided by applicant): Novel roles by glutamatergic receptors in the synaptic effects of beta amyloid Long-term potentiation and depression (LTP and LTD) are promising and widely studied examples of vertebrate synaptic plasticity in which there is a persistent synaptic enhancement or decrement, respectively, seen following brief conditioning periods of synaptic activity. In both these forms of plasticity, which are leading models of memory, NMDA receptors (-Rs) and AMPA receptors (-Rs) at synapses play key and distinct roles. The general aim of this grant has been to examine the subcellular signaling controlling LTP and LTD. Recently, we have found that beta amyloid (A¿), a peptide strongly implicated as a causative agent in Alzheimer's disease, has pronounced effects on AMPA-R trafficking requiring a novel form of NMDA-R signaling. In this grant period, we will examine the different roles played by NMDA-Rs and AMPA-Rs and their associated proteins in the effects of A¿ on synapses. Our preliminary studies show that a non-ionic form of NMDA-R signaling as well as a specific subunit of AMPA-Rs are required for A¿ to modify excitatory synapses. Here we will examine these findings using several complementing methodologies including molecular biology, electrophysiology, and two-photon laser scanning microscopy. These studies will use heterologous cell lines, organotypic rat hippocampal slices and genetically modified mice. The results of these studies will elucidate the mechanisms underlying Alzheimer's disease as well as provide potentially efficacious treatment strategies. The specific aims are to determine: Specific Aim 1: The role played by NMDA-Rs and associated molecules in A¿-induced synaptic depression Specific Aim 2: The role played by AMPA-Rs and associated molecules in A¿-induced synaptic depression