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

项目摘要 运动回路控制基本行为，如吞咽、呼吸和运动。脊髓运动 神经元是将中枢神经系统内产生的运动指令翻译成 外周肌肉目标。运动神经元被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来自大脑的下行通路。在早期发育过程中， 由运动神经元接收的突触活动形成它们的功能特性。相反， 在运动神经元接收神经元布线或突触驱动中引起的扰动通常导致运动神经元 系统紊乱这种情况的一个突出的例子是脊髓性肌萎缩症（SMA）-一种遗传性 由运动神经元存活蛋白（SMN）普遍缺乏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，导致脊髓损伤的异常。 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的潜在机制在很大程度上仍然难以捉摸。我们之前的工作让我们发现了 本体感受起源的功能障碍是疾病过程早期的关键决定性事件。功能受损 感觉-运动兴奋性突触的最终丧失诱导了神经元上通道表达的变化， 运动神经元膜，导致运动输出减少。从而解开了 负责突触功能障碍和损失将提供疾病机制的关键见解。在目标1中， 我们将研究补体蛋白是否是功能障碍的原因，并最终消除 脆弱的突触。为了解决这个问题，我们将采用小鼠遗传学与 形态学和功能测定。在目标2中，我们将研究某些关键经典补语的作用 蛋白质在正常发育过程中的感觉运动回路的组装和完善。我们还将使用 小鼠遗传学，结合形态学和功能测定，完成项目的这一部分。在Aim中 3、我们将探讨可能通过异常激活的细胞因子来引起选择性攻击的分子机制。 在疾病的小鼠模型中，免疫系统在普遍存在的SMN缺陷下对突触的影响。

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.