Glial Mechanisms Of Developmental Synapse Refinement

发育突触细化的神经胶质机制

• 批准号: 10468955
• 负责人: Xianhua Piao
• 金额: $ 56.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468955
• 关键词: ADGR1 gene; Adaptor Signaling Protein; Address; Adhesions; Apoptotic; Astrocytes; Binding; Biochemical; Biological Assay; Brain; Cells; Cellular Assay; Complement Receptor; Couples; Cultured Cells; Data; Defect; Development; Dorsal; Eating; Electrophysiology (science); Exons; Family; Foundations; G-Protein-Coupled Receptors; Genetic Models; Growth; Human; Inhibitory Synapse; Interneurons; Knock-out; Lateral Geniculate Body; Lead; Learning; Length; Life; Ligands; MHC Class I Genes; Maintenance; Measures; Mediating; Memory; Mental disorders; Microglia; Molecular; Mus; Nerve Degeneration; Nervous system structure; Neurodevelopmental Disorder; Neurons; Noise; Pathway interactions; Pediatric Surgical Procedures; Phenotype; Phosphatidylserines; Process; Protein Isoforms; Publishing; RNA Splicing; Receptor Protein-Tyrosine Kinases; Research; Retina; Rodent; Role; Sampling; Shapes; Signal Pathway; Signal Transduction; Specificity; Structure of geniculate ganglion; Supporting Cell; Synapses; Synaptic plasticity; System; Testing; Transcript; Transgenic Mice; Variant; autism spectrum disorder; base; corticogeniculate; density; design; experience; experimental study; fractalkine receptor; genetic manipulation; in vivo; infancy; member; nerve supply; neural circuit; neuronal circuitry; novel; postnatal; presynaptic; receptor; response; retinogeniculate; success; synaptic pruning; synaptogenesis; transcriptome sequencing

Abstract Brain wiring makes us who we are, but our understanding of the wiring mechanism is still in its infancy. Synapses, the structural units for transmitting electrochemical signals between neurons, form the basis of brain wiring and the specificity of synaptic connections determines brain function. During development, the nervous system acquires an excess of synapses that undergoes refinement, to optimize the signal-to-noise ratio. Developmental brain wiring is refined in part through synaptic pruning, which eliminates weak synapses allowing for strengthening of those retained. Synapse formation and elimination also persist in the mature nervous system through experience-dependent structural synaptic plasticity, which is the basis of learning. Therefore, synaptic formation and pruning are crucial not only in shaping neural circuits during development but also in regulating synaptic plasticity in response to experience and memory. Defects in synaptic pruning and maintenance have been implicated in neurodevelopmental disorders and neurodegeneration. Although synapses functionally connect neurons, the glial support cells such as microglia and astrocytes carry out the process of synapse pruning. For example, genetic manipulation of microglial complement and fractalkine receptor pathways in mice has conclusively demonstrated their involvement in synapse pruning. TAMs, a family of three related receptors, are important for astrocytic (but apparently not microglial) synaptic pruning. However, the full spectrum of molecular components involved in this process remains to be defined. GPR56 is a member of the adhesion-GPCR family, conserved between rodents and humans. Our unpublished preliminary studies showed (1) deleting microglial Gpr56 from mouse microglia leads to a significantly increased retinal innervation in dorsal lateral geniculate ganglion (dLGN); (2) GPR56 binds both phosphatidylserine (PtdSer) and the Gla domain of GAS6; and (3) deleting Gas6 leads to a significantly reduced synaptic density in dLGN. TAM receptors require adaptor protein for their interaction with PtdSer and GAS6 is one such adaptor. However, triple deletion of TAM receptors leads to an opposite phenotype from Gas6 knockout. Therefore, we argue that GAS6 does not function through TAM receptors in astrocyte- mediated synaptic pruning. Instead, taking together our preliminary data and others' published results, we hypothesize that GPR56 regulates microglia-mediated developmental synapse refinement by binding to PtdSer and that GAS6 modulates the degree of microglial GPR56 mediated synaptic pruning by competing GPR56- PtdSer interaction. Our present proposal is designed to test this hypothesis using genetic models, electrophysiological analysis, as well as biochemical and cellular assays. The success of the proposed research will establish a novel mechanism and signaling pathway in regulating developmental synapse refinement. We intend to lay the foundation to investigate the role(s) of microglial GPR56 in neurodevelopmental disorders as well as its potential role in neurodegeneration.

抽象的 大脑接线决定了我们是谁，但我们对接线机制的理解仍处于起步阶段。 突触是神经元之间传递电化学信号的结构单元，构成大脑的基础 接线和突触连接的特异性决定了大脑功能。在发育过程中，神经 系统获取过量的突触并进行细化，以优化信噪比。 发育性大脑线路在一定程度上是通过突触修剪来完善的，突触修剪消除了弱突触 允许加强保留的人员。突触的形成和消除也持续存在于成熟细胞中 神经系统通过经验依赖的结构突触可塑性，这是学习的基础。 因此，突触的形成和修剪不仅对于发育过程中神经回路的形成至关重要 还可以调节突触可塑性以响应经验和记忆。突触修剪的缺陷 和维持与神经发育障碍和神经变性有关。虽然 突触在功能上连接神经元，神经胶质支持细胞（例如小胶质细胞和星形胶质细胞）执行 突触修剪的过程。例如，小胶质细胞补体和 fractalkine 的基因操作 小鼠的受体途径已最终证明它们参与突触修剪。 TAM，一个 三个相关受体家族，对于星形胶质细胞（但显然不是小胶质细胞）突触修剪很重要。 然而，该过程中涉及的全部分子成分仍有待定义。 GPR56 是 粘附 GPCR 家族的成员，在啮齿动物和人类之间保守。我们未发表的 初步研究表明（1）从小鼠小胶质细胞中删除小胶质细胞Gpr56会导致显着 背外侧膝状神经节（dLGN）的视网膜神经支配增加； (2) GPR56 结合两者 磷脂酰丝氨酸 (PtdSer) 和 GAS6 的 Gla 结构域； (3) 删除 Gas6 会导致显着 dLGN 中突触密度降低。 TAM 受体需要衔接蛋白才能与 PtdSer 相互作用 GAS6 就是这样的一种适配器。然而，TAM 受体的三重缺失会导致与 Gas6 淘汰赛。因此，我们认为 GAS6 并不通过星形胶质细胞中的 TAM 受体发挥作用。 介导的突触修剪。相反，综合我们的初步数据和其他人发表的结果，我们 假设 GPR56 通过与 PtdSer 结合来调节小胶质细胞介导的发育突触细化 GAS6 通过竞争性 GPR56- 调节小胶质细胞 GPR56 介导的突触修剪程度 PtdSer 相互作用。我们目前的提议旨在使用遗传模型来检验这一假设， 电生理学分析以及生化和细胞测定。提议的成功 研究将建立调节发育突触的新机制和信号通路 细化。我们打算为研究小胶质细胞 GPR56 在 神经发育障碍及其在神经变性中的潜在作用。

项目成果

Assessing for prenatal risk factors associated with infant neurologic morbidity using a multivariate analysis.

使用多变量分析评估与婴儿神经系统发病相关的产前危险因素。

• 发表时间: 2023-12
• 作者: Jain, Samhita;Oltman, Scott;Rogers, Elizabeth;Ryckman, Kelli;Petersen, Mark;Baer, Rebecca J;Rand, Larry;Piao, Xianhua;Jelliffe
• 通讯作者: Jelliffe