Mechanisms of Central Synaptic Dysfunction in SMA

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。我们之前的工作让我们发现了 负责突触丢失的分子机制，部分涉及经典的补体级联。 兴奋性-抑制性神经传递的失衡导致紧张性抑制下的脆弱运动神经元。 重要的是，SMA运动神经元通过细胞自主机制死亡，涉及P53途径、MDM2和 MDM4以及SMN的下游目标Stasimon。然而，分子和细胞机制 SMA小鼠的姿势和运动缺陷的原因尚不清楚。因此解开了分子 负责这两种表型的机制将为疾病机制提供关键的见解。在……里面 目的1，我们将研究多巴胺能突触功能障碍是否与姿势损害有关。 在SMA小鼠身上。为了解决这个问题，我们将使用小鼠遗传学以及形态和功能分析。 在目标2中，我们将研究腹侧脊髓小脑束神经元导致步态和运动障碍的作用。 在SMA小鼠身上。我们还将使用小鼠遗传学，病毒介导的Cre表达，结合形态， 完成项目这一部分的生理和行为分析。在目标3中，我们将探讨分子 涉及CD47和Sirpα的突触丢失的机制及其潜在的协同作用 在小鼠普遍存在的SMN缺乏下，经典补体途径中的起始蛋白C1q 这种疾病的模型。

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 has led us in uncovering part of the molecular mechanisms responsible for synaptic loss, implicating in part the classical complement cascade. Imbalance of excitatory-inhibitory neurotransmission renders vulnerable motor neurons under tonic inhibition. Importantly, SMA motor neurons die through cell-autonomous mechanisms implicating p53 pathway, Mdm2 & Mdm4 as well as Stasimon, a downstream target of SMN. However, the molecular and cellular mechanisms responsible for postural and locomotor deficits in SMA mice are not known. Unraveling therefore the molecular mechanisms responsible for these two phenotypes would provide key insights into the disease mechanisms. In Aim 1, we will study whether dysfunction of dopaminergic synapses is responsible for the postural impairments 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 ventral spinocerebellar tract neurons causing gait and locomotor deficits in SMA mice. We will also use mouse genetics, viral-mediated Cre expression, combined with morphological, physiological and behavioral assays to complete this part of the project. In Aim 3, we will probe into the molecular mechanisms that are responsible for synaptic loss involving CD47 and SIRPα as well as potential synergy with C1q, the initiating protein in the classical complement pathway, under ubiquitous SMN deficiency in mouse models of the disease.