Project 3: Microglia heterogeneity and function in interneuron development

项目 3：小胶质细胞异质性和中间神经元发育中的功能

• 批准号: 10408735
• 负责人: Xianhua Piao
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408735
• 关键词: ADGR1 gene; Address; Adhesions; Anterior; Aorta; Apoptotic; Behavior; Birth; Brain; Brain region; Cell Density; Cell Nucleus; Cells; Cessation of life; Cortical Dysplasia; Crystallization; Cues; Data; Development; Dorsal; Drug Design; Drug Targeting; Exhibits; Family member; Functional disorder; G-Protein-Coupled Receptors; Ganglia; Heterogeneity; Human; Interneurons; Light; Link; Medial; Microglia; Mining; Molecular; Morphology; Mus; Neurodevelopmental Disorder; Neuroglia; Neurons; Pathway interactions; Population; Process; Proliferating; Property; Prosencephalon; Radial; Research; Role; Sampling; Schizophrenia; Small Nuclear RNA; Somatosensory Cortex; Spatial Distribution; Structure; TLR10 gene; Testing; Third Pregnancy Trimester; TimeLine; Toll-like receptors; Transcript; Transgenic Mice; Work; Yolk Sac; age related; autism spectrum disorder; brain cell; brain tissue; cell growth regulation; cell type; conditional knockout; lateral ventricle; lateral ventricle body; macrophage; migration; mouse model; nerve stem cell; neural circuit; neuropsychiatric disorder; novel; postnatal; progenitor; single-cell RNA sequencing; success; transcriptome sequencing; transcriptomics; translational potential

Abstract Neural circuits require precise placement of correct numbers of interneurons (INs). This delicate process is derailed in neurodevelopmental and neuropsychiatric disease. Microglia, the brain resident macrophages, influence many aspects of brain development, including genesis, migration and maturation of cortical interneurons (cINs). In our preliminary study leading up to this proposal, we discovered diverse molecular and cellular properties of human microglia in the developing forebrain and we found that specific molecularly- defined subtypes are differentially distributed across brain regions. Furthermore, our results show that GPR56 expression defines a subset of human microglia and that deletion of murine microglial Gpr56 leads to a significant reduction in the numbers of PV+ interneurons in specific brain region. However, the full scope of microglia transcriptomic and functional heterogeneity, especially in the human brain, remains elusive. The proposed research will establish the postnatal cellular and molecular heterogeneity of microglia in the human caudal and medial ganglionic eminence with a specific focus on GPR56 in microglia. We hypothesize that microglial GPR56 promotes interneuron development. To test this and corollary hypotheses, we will carry out the following three aims: (1) Define microglia morphology, distribution, and their interactions with neural progenitors (NPCs) and young neurons in the human GEs and the Arc (a unique cluster of migratory interneurons found at birth in the vicinity of the human lateral ventricles); (2) Characterize microglial transcriptomic heterogeneity in the developing hMGE, hCGE and the Arc; and (3) Investigate the cell-type- specific function of microglial GPR56 in interneuron development using microglia-specific conditional knockout mouse model. Most meaningfully, we are conducting our studies using both human brain tissues and transgenic mouse models, to take advantage of the many manipulations that can be done in mice, but always grounding our work in the human conditions we seek to understand. The success of the proposed research will open a novel and important line of research into the origin of neurodevelopmental disorders, such as autism and schizophrenia. Given the status of aGPCRs as drug targets, this line of research carries tremendous translational potential. In particular, it is feasible to begin designing drugs that modify the action of GPR56 given the discovery of its crystal structure.

抽象的 神经回路需要精确放置正确数量的中间神经元 (IN)。这个微妙的过程是 神经发育和神经精神疾病脱轨。小胶质细胞，大脑中常驻的巨噬细胞， 影响大脑发育的许多方面，包括皮质的发生、迁移和成熟 中间神经元（cIN）。在我们提出这一建议的初步研究中，我们发现了多种分子和 人类小胶质细胞在发育中的前脑中的细胞特性，我们发现特定的分子- 定义的亚型在不同大脑区域的分布存在差异。此外，我们的结果表明 GPR56 表达定义了人类小胶质细胞的一个子集，而小鼠小胶质细胞 Gpr56 的缺失会导致 特定大脑区域的 PV+ 中间神经元数量显着减少。然而，完整的范围 小胶质细胞转录组和功能异质性，尤其是在人脑中，仍然难以捉摸。这 拟议的研究将确定人类小胶质细胞的出生后细胞和分子异质性 尾部和内侧神经节隆起，特别关注小胶质细胞中的 GPR56。我们假设 小胶质细胞 GPR56 促进中间神经元发育。为了检验这一点和推论假设，我们将进行 以下三个目标：（1）定义小胶质细胞的形态、分布及其与神经元的相互作用 人类 GE 和 Arc（一种独特的迁移细胞群）中的祖细胞 (NPC) 和年轻神经元 出生时在人类侧脑室附近发现的中间神经元）； (2) 表征小胶质细胞 发育中的 hMGE、hCGE 和 Arc 的转录组异质性； (3) 研究细胞类型- 使用小胶质细胞特异性条件敲除研究小胶质细胞 GPR56 在中间神经元发育中的特异性功能 鼠标模型。最有意义的是，我们正在使用人类脑组织和 转基因小鼠模型，利用可以在小鼠身上进行的许多操作，但总是 将我们的工作立足于我们寻求了解的人类状况。拟议研究的成功将 为自闭症等神经发育障碍的起源开辟一条新颖且重要的研究路线 和精神分裂症。鉴于 aGPCR 作为药物靶标的地位，这一研究方向具有巨大的意义 翻译潜力。特别是，开始设计改变 GPR56 作用的药物是可行的 鉴于其晶体结构的发现。