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Investigating CD47-SIRPa as novel protective signals during CNS synaptic pruning

研究 CD47-SIRPa 作为 CNS 突触修剪过程中的新型保护信号

基本信息

批准号：
9032548
负责人：
Beth Ann Stevens
金额：
$ 58.65万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2015-03-15 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9032548
关键词：
Address Adult Affect Age Apoptotic Autoimmunity Behavior Behavioral Binding Brain CD47 gene Cells Complement Complement 1q Complement Receptor Corpus striatum structure Cues Data Defect Detection Development Developmental Process Disease Disease Progression Down-Regulation Eating Electrophysiology (science)Employee Strikes Ensure Excision Exhibits Health Huntington Disease Immune Immune response Immune system In Vitro Inflammation Knockout Mice Lead Macrophage-1 Antigen Mediating Microglia Modeling Molecular Mus Neurodegenerative Disorders Neurons Pathway interactions Patients Phagocytes Phagocytosis Phosphorylation Process Regulation Research Signal Transduction Specificity Synapses Techniques Testing Visual system structure Work genetic manipulation in vivo insight macrophage mouse model neural circuit novel overexpression pathogen postnatal presynaptic prevent programs receptor relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): Microglia, the brain's resident immune cells and phagocytes, are emerging as critical regulators of developing synaptic circuits in the healthy brain. Recent studies from our lab and others indicate that microglia engulf synapses in the developing brain; however, how microglia know which synapses to target remains a major open question. Our previous work demonstrates that microglia-mediated pruning underlies developmental synaptic refinement, an essential process required for the formation of mature circuits in which weak or inappropriate synapses are eliminated and remaining connections are maintained and strengthened. We found that microglial engulfment of presynaptic inputs is activity-dependent and driven by complement molecules C1q and C3, and microglial complement receptor CR3. These molecules are innate immune "eat me" signals known for promoting macrophage phagocytosis of apoptotic cells or debris, and mice lacking these signals exhibit reduced microglial engulfment of synaptic inputs and impaired refinement. This suggests that microglia-mediated pruning may be analogous to the removal of non-self material by phagocytes in the immune system. However, we do not yet know how microglia precisely determine which inputs to engulf and which to avoid, an important decision regarding the specificity needed to sculpt precise, mature connections. We propose that protective "don't eat me" signals are required to prevent inappropriate microglial engulfment of necessary connections during synaptic refinement, just as they prevent inappropriate engulfment of healthy self-cells by phagocytes during an immune response. Our preliminary data support this hypothesis, as "don't eat me" signals CD47 and SIRP are present in the developing brain and required to prevent excess microglial engulfment of synaptic inputs. We will investigate the anatomical, functional, and behavioral abnormalities in mice lacking CD47 and SIRP to better understand the consequences of excess microglial engulfment. We will also investigate whether and how these "don't eat me" signals are regulated by activity to determine if they direct microglia to engulf specific synapses in an activity-dependent manner. Finally, as "don't eat me" signals are known to be downregulated in the brains of patients with neurodegenerative diseases, we will examine whether these molecules are dysregulated in mouse models of Huntington's disease (HD) and could thereby underlie synapse loss caused by aberrant microglial engulfment. This study would be the first to demonstrate that synaptic protection is required to prevent inappropriate microglial engulfment of necessary connections during development. This research program will provide insight not only into the mechanisms regulating microglial engulfment of specific synapses, but also into possible mechanisms underlying synapse loss in CNS neurodegenerative diseases.