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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：
9129820
负责人：
Yutaka Yoshida
金额：
$ 2.5万
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：
2015-09-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9129820
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.