Motoneuron mortality in neurodegenerative diseases induced by homeostatic dysregulation of excitability

神经退行性变中运动神经元选择性易损性的多种机制已被提出 疾病。在反思我们实验室之前的工作，以及我们在世界各地的同事们的工作 在世界范围内，我们开发了一个综合假说，它解释了绝大多数已报道的发现。我们 提出小鼠运动神经元对突变蛋白的净反应是对 动态平衡可塑性。这表现为上调和下调对 旨在控制运动神经元活动水平的补偿机制。收益的毒害增长 功能导致过度补偿和戏剧性的动态平衡振荡 运动神经元病变。此外，我们认为，这些补偿机制的规模扩大导致了 观察到最大运动神经元的脆弱性更大。该项目的目标是提供严格的测试 使用突变的SOD1小鼠作为神经退行性变的模型系统的这一新的失调假说 不成比例地针对运动神经元的疾病。拟议的实验在很大程度上依赖于我们最近 使我们能够在整个过程中对小鼠运动神经元进行细胞内记录的技术突破 疾病进展，从新生儿到成人，使用体内和体外制剂，以及我们的 在评估运动神经元的膜通道密度和空间分布方面的专业知识。我们的 方法包括提出一系列对运动神经元兴奋性的“内环境平衡挑战”，并比较 MSO1运动神经元对野生型对照的代偿反应。如果我们的假设是正确的， 我们期望观察到mSOD1运动神经元对每一个 这些mSOD1反应随着运动神经元的大小而扩大。一共有三个 具体目的：评估mSOD1和对照运动神经元对药物扰动的反应 运动神经元的固有电特性(目标1)、运动神经元的突触输入(目标2)和 运动神经元的神经调节输入(目标3)。由此产生的数据将为追求 激进的、新的治疗策略以及阐明特定的信号转导级联反应 在不同的动态平衡机制下。

Multiple mechanisms has been proposed for the selective vulnerability of motoneurons in neurodegenerative diseases. In reflecting on the prior work from our laboratories, as well as that of our colleagues around the world, we have developed a synthetic hypothesis that accounts for a vast majority of the reported findings. We propose that the net response of mouse motoneurons to the presence of mutant proteins is a disregulation of homeostatic plasticity. This manifests as an increased `gain' of both the up- and down-regulation of compensatory mechanisms designed to control the level of motoneuronal activity. The toxic increase of gain function leads to overcompensation and a dramatic cascade of homeostatic oscillations that increases motoneuron morbidity. Further, we propose that size-scaling of these compensatory mechanisms leads to the observed greater vulnerability of the largest motoneurons. The goal of this project is to provide rigorous testing of this novel disregulation hypothesis using mutant SOD1 mice as a model system for neurodegenerative diseases that disproportionately target motoneurons. The proposed experiments rest heavily on our recent technical breakthroughs that enable us to perform intracellular recordings of mouse motoneurons throughout disease progression, from neonate through adult, using both in vivo and in vitro preparations, as well as our expertise in assessing the density and spatial distributions of membrane channels in motoneurons. Our approach entails presenting a series of `homeostatic challenges' to motoneuron excitability and comparing the compensatory responses of mSOD1 motoneurons to those of wild-type controls. If our hypothesis is correct, we expect to observe that mSOD1 motoneurons exhibit consistently greater responses to each of the challenges than do wild-types and that these mSOD1 responses scale with motoneuron size. There are three specific aims: to assess the responses of mSOD1 and control motoneurons to drug perturbations that alter the intrinsic electrical properties of motoneurons (Aim 1), the synaptic inputs to motoneurons (Aim 2) and the neuromodulatory inputs to motoneurons (Aim 3). The resulting data will provide a strong impetus for pursuing radical, novel therapeutic strategies as well as for elucidating the specific signal transduction cascades underlying the different homeostatic mechanisms.