Mechanisms of synaptic loss by the classical complement pathway in motor circuit development and disease

项目摘要 马达电路控制吞咽、呼吸和运动等基本行为。脊椎运动 神经元是将中枢神经系统内产生的运动指令转换为 外周肌肉靶标。运动神经元由一种精确调节的突触活动模式激活 感觉神经元、局部脊髓中间神经元和大脑下行通路。在早期发育过程中， 运动神经元接收到的突触活动决定了它们的功能特性。相比之下，基因突变 运动神经元接收到的神经元连接或突触驱动的诱导扰动通常会导致运动 系统紊乱。这种情况的一个突出例子是脊髓性肌萎缩症(SMA)--一种遗传性 由于存活运动神经元(SMN)蛋白普遍缺乏而引起的神经肌肉疾病。SMA 发病机制涉及运动回路的多个组成部分的改变，导致脊柱异常 反射、运动神经元丧失和骨骼肌萎缩。然而，分子、细胞和电路 SMA背后的机制在很大程度上仍然难以捉摸。我们之前的工作使我们发现了突触 本体感觉起源的功能障碍是疾病进程早期的关键决定事件。功能受损 而感觉-运动兴奋性突触的最终丧失会导致通道表达的改变 运动神经元膜，导致运动输出减少。因此，解开了分子机制 对突触功能障碍和丢失的责任将为疾病机制提供关键的见解。在目标1中， 我们将研究补体蛋白是否对功能障碍负责，并最终消除 在SMA小鼠中存在脆弱的突触。为了解决这个问题，我们将利用老鼠遗传学和 形态分析和功能分析。在目标2中，我们将研究某些关键的经典补语的作用 在正常发育过程中感觉-运动回路的组装和精炼的蛋白质。我们还将使用 老鼠遗传学，结合形态和功能分析来完成该项目的这一部分。在AIM 3，我们将探讨导致选择性攻击的分子机制可能通过异常激活 在无处不在的SMN缺乏症小鼠模型中，免疫系统向突触靠拢。

Project Summary Motor circuits control fundamental behaviors such as swallowing, breathing and locomotion. Spinal motor neurons are the key mediators translating motor commands generated within the central nervous system to peripheral muscle targets. Motor neurons are activated by a precisely regulated pattern of synaptic activity from sensory neurons, local spinal interneurons and descending pathways from the brain. During early development, synaptic activity received by motor neurons shapes their functional properties. In contrast, gene mutations that induce perturbations in either neuronal wiring or synaptic drive received by motor neurons often result in motor system disorders. A prominent example of this situation is spinal muscular atrophy (SMA)—an inherited neuromuscular disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. SMA pathogenesis involves alterations of multiple components of the motor circuit leading to abnormalities in spinal reflexes, motor neuron loss and skeletal muscle atrophy. However, the molecular, cellular and circuit mechanisms underlying SMA remain largely elusive. Our previous work have led us in uncovering synaptic dysfunction of proprioceptive origin as a key determinant event early in the disease process. Impaired function and eventual loss of the sensory-motor excitatory synapses induce changes in the expression of channels on the motor neuron membrane, resulting in reduced motor output. Unraveling therefore the molecular mechanisms responsible for synaptic dysfunction and loss would provide key insights into the disease mechanisms. In Aim 1, we will study whether complement proteins are responsible for the dysfunction and ultimately the elimination of vulnerable synapses in in SMA mice. To address this, we will employ mouse genetics together with morphological and functional assays. In Aim 2, we will investigate the role of certain key classical complement proteins in the assembly and refinement of sensory-motor circuits during normal development. We will also use mouse genetics, combined with morphological and functional assays to complete this part of the project. In Aim 3, we will probe into the molecular mechanisms that may cause the selective attack by aberrant activation of the immune system towards synapses under ubiquitous SMN deficiency in mouse models of the disease.