Synapse Engulfment by Oligodendrocyte Precursor Cells: A New Mechanism of Circuit Refinement in the Developing Brain

少突胶质细胞前体细胞突触吞噬：发育中大脑中电路细化的新机制

基本信息

批准号：
10637731
负责人：
Lucas M Cheadle
金额：
$ 63.68万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637731
关键词：
Ablation Age Animal Behavior Animals Astrocytes Axon Behavioral Assay Biological Biological Models Brain Brain Diseases CRISPR screen Cell physiology Cells Child Complex Data Development Disease Economic Burden Excision Eye Foundations Future Goals Health Healthcare Healthcare Systems Human Impairment Individual Life Light Link Longevity Mediating Microglia Modernization Molecular Monitor Mus Nature Neurobiology Neurodevelopmental Disorder Neuroglia Neurologic Neurons Neurophysiology - biologic function Neurosciences Oligodendroglia Pathway interactions Phagocytes Phagocytosis Phase Physiological Play Population Prevalence Process Property Role Route Sensory Shapes Symptoms Synapses Techniques Testing Therapeutic Time Transgenic Organisms United States Viral Genes Visual Visual Cortex Visual System Work autism spectrum disorder brain cell care burden critical period experience experimental study in vivo insight interdisciplinary approach multidisciplinary myelination nerve stem cell neural circuit novel novel therapeutic intervention oligodendrocyte precursor optogenetics pharmacologic postnatal postnatal development precursor cell receptor response spatiotemporal symptomatic improvement targeted treatment therapy development tool transcriptomics treatment strategy two photon microscopy

项目摘要

PROJECT SUMMARY The establishment of synaptic connectivity during brain development involves the initial formation of an overabundance of synapses followed by a refinement process in which some of these synapses are maintained while others are eliminated. The precise elimination of excess synapses is driven by sensory experience during critical periods of early postnatal life. Impairments in sensory-dependent synapse elimination contribute to neurodevelopmental disorders such as autism, underscoring the importance of this process for the proper development and function of neural circuits. However, although neurodevelopmental disorders are growing in prevalence at an alarming rate, therapeutic strategies for treating them are scarce in part due to a lack of insight into the factors that control synapse elimination in the healthy brain. A key goal of this proposal is to uncover novel cellular and molecular mechanisms underlying the elimination of synapses downstream of experience, thereby laying the groundwork for new therapeutic approaches to treat disorders of postnatal brain development. Work in the visual system of the mouse has revealed that non-neuronal brain cells, predominantly microglia and astrocytes, coordinate synapse elimination before the onset of visual experience by phagocytosing excess synapses. However, data suggest that these cells may not be major regulators of synapse elimination during late phases of development that are coordinated by visual experience. On the contrary, we recently discovered a key role for a less well understood class of glia, oligodendrocyte precursor cells (OPCs), in eliminating synapses in response to experience through synaptic phagocytosis. This result is consistent with wide-spread speculation that OPCs, while predominantly appreciated for their differentiation into mature oligodendrocytes, play key roles in the brain beyond myelination. In line with this possibility, our data suggest that OPCs are essential for shaping functional neural circuits during the maturation of the brain. In this application, we propose a multi-disciplinary strategy to test the hypothesis that the engulfment of synapses by OPCs is a core mechanism underlying the sensory-dependent elimination of functional synapses in the developing brain. In Aim 1, we will employ viral and transgenic tools to characterize the spatio-temporal dynamics and activity-dependent basis of synaptic engulfment by OPCs using in vivo two-photon microscopy. In Aim 2, we will apply physiological and behavioral assays to determine the consequences of synaptic engulfment by OPCs on brain function in the intact animal. In Aim 3, we will merge unbiased transcriptomic and CRISPR- based screening techniques with a candidate-based approach focused on the phagocytic receptor Lrp1 to reveal molecular pathways underlying the engulfment of synapses by OPCs. Altogether, we expect these studies to establish synapse engulfment by OPCs as a new mechanism linking experience to neural circuit development, and to lay the foundation for future studies geared toward modifying OPC function as a potential therapeutic strategy for treating neurodevelopmental disorders.

项目概要大脑发育过程中突触连接的建立涉及到突触连接的最初形成突触过多，随后进行细化过程，其中一些突触得以保留而其他人则被淘汰。多余突触的精确消除是由感官体验驱动的产后早期生命的关键时期。感觉依赖性突触消除的损伤有助于神经发育障碍，如自闭症，强调了这个过程对于正确的重要性神经回路的发育和功能。然而，尽管神经发育障碍在患病率惊人，治疗策略稀缺，部分原因是缺乏洞察力研究控制健康大脑中突触消除的因素。该提案的一个关键目标是发现消除经验下游突触的新细胞和分子机制，从而为治疗产后大脑发育障碍的新治疗方法奠定了基础。对小鼠视觉系统的研究表明，非神经元脑细胞，主要是小胶质细胞和星形胶质细胞，在视觉体验出现之前通过吞噬协调突触消除多余的突触。然而，数据表明这些细胞可能不是突触消除的主要调节者在发育的后期阶段，由视觉体验协调。相反，我们最近发现了一种不太为人所知的神经胶质细胞——少突胶质细胞前体细胞（OPC）在通过突触吞噬作用消除突触以响应经验。这个结果与人们广泛猜测 OPC，虽然主要因其分化为成熟的少突胶质细胞在髓鞘形成之外的大脑中发挥着关键作用。根据这种可能性，我们的数据表明 OPCs 对于大脑成熟过程中塑造功能性神经回路至关重要。在此应用中，我们提出了一种多学科策略来检验以下假设： OPCs 突触是功能性突触感觉依赖性消除的核心机制在发育中的大脑中。在目标 1 中，我们将采用病毒和转基因工具来表征时空使用体内双光子显微镜观察 OPC 突触吞噬的动力学和活动依赖性基础。在目标 2，我们将应用生理和行为分析来确定突触吞噬的后果 OPCs 对完整动物大脑功能的影响。在目标 3 中，我们将合并公正的转录组学和 CRISPR- 基于筛选技术，采用基于候选的方法，重点关注吞噬细胞受体 Lrp1，以揭示 OPC 吞噬突触的分子途径。总而言之，我们希望这些研究能够建立 OPC 突触吞噬作为将经验与神经回路发育联系起来的新机制，并为未来旨在改变 OPC 功能作为潜在治疗方法的研究奠定基础治疗神经发育障碍的策略。