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

运动回路发育和疾病中经典补体途径突触损失的机制

基本信息

批准号：
10207406
负责人：
George Z Mentis
金额：
$ 62.24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207406
关键词：
Address Affect Afferent Neurons Age Antibodies Behavior Behavioral Biological Assay Breathing Cause of Death Classical Complement Pathway Complement Complement 1q Confocal Microscopy Data Deglutition Development Disease Disease model Event Excision Excitatory Synapse Fluorescent in Situ Hybridization Functional disorder Gene Mutation Genes Genetic Health Human Immune system Immunohistochemistry Impairment Induced Mutation Infant Inherited Interneurons Locomotion MERTK gene Mediating Mediator of activation protein Membrane Molecular Molecular Biology Morphology Motor Motor Neurons Motor output Movement Mus Muscle Neuraxis Neurodegenerative Disorders Neuromuscular Diseases Neuronal Dysfunction Neurons Output Pathogenesis Pathologic Pattern Peripheral Phenotype Physiological Process Property Proteins Regulation Reporting Role SMN deficiency SMN protein (spinal muscular atrophy)SMN1 gene Sensory Shapes Site Specificity Spinal Spinal Cord Spinal Muscular Atrophy Synapses System Testing Translating Wild Type Mouse Work base brain pathway design designer receptors exclusively activated by designer drugs disease phenotype experimental study human disease immune activation in vivo infancy insight knock-down motor neuron function mouse genetics mouse model multidisciplinary neural circuit neuron loss neuronal circuitry neurotransmission novel postnatal development skeletal muscle wasting spinal reflex synaptic pruning tetanospasmin

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 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.

项目总结