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

• 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
• 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

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.

项目摘要 大脑发育过程中建立突触连通性涉及的初始形成 突触过多，然后进行完善过程，其中一些突触被维持 而其他人则被淘汰。多余的突触的精确消除是由感官体验驱动的 早期产后生活的关键时期。感觉依赖性突触消除的损害有助于 神经发育障碍，例如自闭症，强调了此过程的重要性 神经回路的发展和功能。但是，尽管神经发育障碍正在增长 以惊人的速度患病率，治疗治疗的治疗策略很少，部分原因是缺乏洞察力 进入控制健康大脑中消除突触的因素。该提议的关键目标是发现 消除经验下游突触的新型细胞和分子机制， 从而为治疗产后脑发育障碍的新治疗方法奠定了基础。 在小鼠视觉系统中的工作表明，非神经元细胞主要是 小胶质细胞和星形胶质细胞，在视觉体验开始之前通过吞噬细胞的坐标突触消除 多余的突触。但是，数据表明这些细胞可能不是突触消除的主要调节剂 在后期的开发阶段，通过视觉体验协调。相反，我们最近 发现了知识不足类的神经胶质细胞，少突胶质前体细胞（OPC）的关键作用， 通过突触吞噬作用消除突触以响应经验。这个结果与 广泛的猜测OPC，而主要因其分化为成熟的猜测 少突胶质细胞，在髓鞘中扮演关键角色。根据这种可能性，我们的数据表明 OPC对于在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，以检验以下假设。 OPC突触是一种核心机制，是感觉依赖性消除功能突触的基础机制 在发展中的大脑中。在AIM 1中，我们将使用病毒和转基因工具来表征时空 OPC使用体内两光子显微镜的OPC突触吞噬的动力学和活动依赖性基础。在 AIM 2，我们将应用生理和行为分析来确定突触吞噬的后果 通过OPC对完整动物的脑功能。在AIM 3中，我们将合并公正的转录组和CRISPR- 采用基于候选的方法的基于吞噬受体LRP1的筛查技术揭示 OPC吞没突触的基础的分子途径。总之，我们希望这些研究能够 建立OPC的突触吞没是一种将经验与神经回路发展联系起来的新机制， 并为未来的研究奠定基础，旨在修改OPC功能作为潜在的治疗 治疗神经发育障碍的策略。