Mechanisms of Central Synaptic Dysfunction in SMA

SMA 中枢突触功能障碍的机制

基本信息

批准号：
10200900
负责人：
George Z Mentis
金额：
$ 44.38万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200900
关键词：
Address Affect Afferent Neurons Age Antibiotics Autopsy Behavior Behavioral Biological Assay Breathing Calcineurin Cause of Death Deglutition Development Disease Distal Down-Regulation Engineering Enzymes Equilibrium Event Excitatory Synapse Frequencies Functional disorder Gene Mutation Genes Genetic Glutamate Receptor Glutamates Health Human Immunohistochemistry Impairment In Vitro Individual Induced Mutation Infant Inherited Inhibitory Synapse Interneurons Link Locomotion Maintenance Measures Mediator of activation protein Molecular Morphology Motor Motor Neurons Movement Mus Muscle Nature Neuraxis Neurodegenerative Disorders Neuromuscular Diseases Neuronal Dysfunction Neurons Neurotrophin 3 Onset of illness Output Pathogenesis Pathogenicity Patients Pattern Peripheral Pharmacology Phenotype Physiological Potassium Channel Preparation Property Proprioceptor Protocols documentation Receptor Activation Regulation Reporting Role SMN deficiency SMN protein (spinal muscular atrophy)SMN1 gene Severities Shapes Source Spinal Spinal Cord Spinal Muscular Atrophy Synapses System Testing Therapeutic Intervention Translating Up-Regulation Viral Vector Werdnig-Hoffmann Disease Work brain pathway clinically relevant delayed rectifier potassium channel density design experimental study human disease improved in vivo infancy insight motor disorder mouse genetics mouse model multidisciplinary neuron loss neuronal cell body neuronal circuitry neurotrophic factor novel overexpression protein expression recruit skeletal muscle wasting spinal reflex voltage clamp

项目摘要

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 novel molecular perturbations involving the downregulation of the "delayed rectifier" potassium channel Kv2.1 as an important determinant in the regulation of motor neuron firing. In addition, SMA motor neurons are under increased tonic inhibitory originating from pre-motor inhibitory interneurons. Finally, we have identified reduction of neurotrophin 3 (NT3) as a candidate for the selective vulnerability of motor circuits responsible for activating proximal muscles which are more vulnerable compared to distal muscles. In Aim 1, we will study whether increased inhibitory synaptic drive on motor neurons, acting non-cell autonomously, is responsible for motor circuit dysfunction in SMA mice. We will employ mouse genetics together with morphological and functional assays. In Aim 2, we will investigate whether the dynamic downregulation of the potassium "delayed rectifier" channel Kv2.1 expression through abnormal dephopshorylation is a major contributor for the reduction in MN repetitive firing in SMA. We will use ES-differentiated motor neurons co-cultured with interneurons that have been engineered to downregulate SMN protein levels following antibiotic exposure. In addition, we will use mouse models to determine the contribution of the main three enzymes reported to regulate Kv2.1 expression in neurons. In Aim 3, we will expand on our preliminary studies, which has identified reduction of NT3 in SMA spinal cords early in the disease onset, to determine its relative contribution in the selective vulnerability of motor circuits in SMA mice. Specific and selective upregulation of NT3 in motor neurons or muscles will provide further insights into the source of NT3 impairment.

项目摘要电路电路控制基本行为，例如吞咽，呼吸和运动。脊柱电动机神经元是转化中枢神经系统中产生的电动机命令的关键介质周围肌肉目标。运动神经元被精确调节的突触活动激活从感觉神经元，局部脊柱中间神经元和从大脑降低的途径。在早期发育，运动神经元收到的突触活动塑造其功能特性。相反，基因通常会影响运动神经元接收到神经元接线或突触驱动的突变导致运动系统疾病。这种情况的一个重要例子是脊柱肌肉萎缩（SMA） - 一个生存运动神经元（SMN）蛋白质中普遍缺乏引起的遗传神经肌肉疾病。 SMA发病机理涉及运动电路的多个组件的改变，导致异常脊柱反射，运动神经元丧失和骨骼肌萎缩。但是，分子，细胞和电路 SMA的机制在很大程度上仍然是弹性。我们以前的作品导致我们揭示了小说分子扰动涉及“延迟整流器”钾通道Kv2.1的下调运动神经元射击调节中的重要确定器。此外，SMA运动神经元下方增加的抑制性抑制性来自运动前抑制性中间神经元。最后，我们已经确定了降低神经营养蛋白3（NT3），作为负责运动电路的选择性脆弱性的候选者与不同肌肉相比，激活近端肌肉更容易受到伤害。在AIM 1中，我们将学习运动神经元上抑制性合成驱动的增加是否自动起作用 SMA小鼠的电动电路功能障碍。我们将采用小鼠遗传学以及形态学和功能测定。在AIM 2中，我们将调查钾的动态下调是否延迟整流器“通过异常去骨术的表达通道Kv2.1表达是降低的主要因素在MN在SMA中重复射击。我们将使用与中间神经元共培养的ES分化的运动神经元已设计为在抗生素暴露后下调SMN蛋白水平。此外，我们将使用小鼠模型来确定据报道调节Kv2.1的主要三种酶的贡献在神经元中的表达。在AIM 3中，我们将扩展我们的初步研究，这已经确定 SMA脊髓的NT3早期疾病发作，以确定其在选择性中的相对贡献 SMA小鼠运动电路的脆弱性。运动神经元中NT3的特定和选择性上调或肌肉将进一步了解NT3障碍的来源。