Synapse elimination in the central nervous system

中枢神经系统中的突触消除

基本信息

批准号：
8944229
负责人：
Yutaka Yoshida
金额：
$ 34.52万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8944229
关键词：
Address Adult Affect Animal Model Area Autistic Disorder Automobile Driving Axon Brain Child Data Defect Development Disease Distal Epilepsy Exhibits Fiber Forearm Future Genes Goals Human Impairment Injury Instruction Interneurons Interruption Intervention Knowledge Lead Ligands Link Mediating Molecular Monomeric GTP-Binding Proteins Motor Motor Activity Motor Cortex Motor Neurons Motor Pathways Motor Skills Movement Mus Muscle Mutant Strains Mice Neuraxis Neurons Nociception Pathway interactions Pattern Physiological Play Population Process Quality of life Rabies Regulation Role Semaphorins Signal Transduction Source Spinal Spinal Cord Spinal cord injury Stimulus Stroke Suid Herpesvirus 1 Synapses Testing Wild Type Mouse Work autonomic reflex base design disability gray matter improved in vivo insight kinematics motor deficit mutant nervous system disorder neural circuit novel novel therapeutics postnatal prevent protein expression public health relevance receptor relating to nervous system somatosensory spinal pathway synaptic failure

项目摘要

DESCRIPTION (provided by applicant): Corticospinal neurons, the key conveyers of motor instructions controlling voluntary movement, originate in layer V of the motor cortex and are the major efferent source of descending motor pathways. The overall goal of this proposal is to understand the role of synapse elimination in establishment of corticospinal motor circuits and voluntary movement control. During brain development there is an overabundance of synapse number. However the brain must eliminate excess synapses so that different brain areas can develop specific functions, and avoid stimuli overload. We are just beginning to recognize that improper synapse elimination contributes to neurological disorders such as epilepsy, autism and schizophrenia1-7. However, there are large gaps in our knowledge of the role played by synapse elimination in normal circuit formation and how deficiencies in synapse elimination cause aberrant neural circuit formation and function in vivo. We have recently established unique animal models harboring synapse elimination defects by selectively manipulating genes in specific neural populations during development. Our Preliminary Data implicate regulation of activity-dependent corticospinal synapse elimination by interaction between the transmembrane semaphorin Sema6D and its plexinA1 (PlexA1) receptor. We found that during early postnatal development, CS axons transiently form synapses with spinal neurons. However, these synapses are not eliminated in mice lacking the receptor PlexA1. Importantly, PlexA1 mutants exhibit disrupted skilled movements. Thus we hypothesize that Sema6D-PlexA1-mediated synapse elimination of required for proper patterns of muscle activity during skilled movements. The first aim will determine whether Sema6D-PlexA1 signaling controls synapse elimination via RhoA in an activity-dependent manner. The second aim will examine whether synapses between corticospinal neurons and specific classes of spinal neurons are eliminated by Sema6D-PlexA1 signaling. Finally the third aim will determine whether the Sema6D-PlexA1-mediated CSN synapse elimination is required for co//rrect patterns of muscle activity for skilled movements.

描述（由申请人提供）：皮质脊髓神经元是控制随意运动的运动指令的关键传递者，起源于运动皮层的第五层，是下行运动通路的主要传出源。本提案的总体目标是了解其作用。突触消除在建立皮质脊髓运动回路和自主运动控制中的作用在大脑发育过程中，突触数量过多，但大脑必须消除多余的突触，以便不同的大脑区域。我们刚刚开始认识到，不当的突触消除会导致癫痫、自闭症和精神分裂症等神经系统疾病1-7。然而，我们对突触消除所发挥的作用的了解还存在很大差距。我们最近通过选择性地操纵特定神经群体中的基因，建立了具有突触消除缺陷的独特动物模型。我们的初步数据表明，跨膜信号蛋白 Sema6D 与其 plexinA1 (PlexA1) 受体之间的相互作用可调节活动依赖性皮质脊髓突触消除，我们发现在出生后早期发育过程中，CS 轴突会短暂地与脊髓神经元形成突触。缺乏受体 PlexA1 的小鼠中不会被消除。重要的是，PlexA1 突变体表现出熟练的运动被破坏。密切关注的是，在熟练运动过程中，Sema6D-PlexA1 介导的突触消除是正确的肌肉活动模式所必需的。第一个目标将确定 Sema6D-PlexA1 信号是否以活动依赖性方式通过 RhoA 控制突触消除。 Sema6D-PlexA1 信号传导消除了皮质脊髓神经元和特定类别的脊髓神经元之间的相互作用。最后，第三个目标将确定 Sema6D-PlexA1 是否介导。 CSN 突触消除对于协调熟练运动的肌肉活动模式是必需的。