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.

摘要 大脑的线路决定了我们是谁，但我们对线路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位，是大脑的基础 神经线路和突触连接的特异性决定了大脑的功能。在发育过程中，神经 系统获得了过量的突触，这些突触经过细化，以优化信噪比。 发育中的大脑线路部分是通过突触修剪来完善的，这会消除弱突触 以加强那些被保留的。突触的形成和消除也在成熟的 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在发育过程中塑造神经回路方面至关重要， 而且在调节突触可塑性以响应经验和记忆方面也是如此。突触修剪缺陷 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，胶质支持细胞如小胶质细胞和星形胶质细胞执行突触的功能。 突触修剪的过程。例如，小胶质细胞补体和fractalkine的遗传操作 受体通路的研究已经最终证明了它们参与突触修剪。TAM，a 三个相关受体的家族，对于星形胶质细胞（但显然不是小胶质细胞）突触修剪是重要的。 然而，参与这一过程的分子组分的全谱仍有待确定。GPR 56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 初步研究表明：（1）从小鼠小胶质细胞中删除小胶质细胞Gpr 56， 在背外侧膝状体神经节（dLGN）中增加的视网膜神经支配;（2）GPR 56结合 磷脂酰丝氨酸（PtdSer）和GAS 6的Gla结构域;和（3）缺失GAS 6导致GAS 6的显著减少。 dLGN中突触密度降低。TAM受体需要衔接蛋白与PtdSer相互作用， GAS 6就是这样一个适配器。然而，TAM受体的三重缺失导致与表型相反的表型， Gas 6击倒。因此，我们认为GAS 6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，结合我们的初步数据和其他人发表的结果，我们 推测GPR 56通过与PtdSer结合来调节小胶质细胞介导发育性突触精细化 GAS 6通过竞争GPR 56 - 1调节小胶质细胞GPR 56介导的突触修剪的程度。 PtdSer相互作用。我们目前的建议旨在使用遗传模型来测试这一假设， 电生理分析以及生物化学和细胞测定。建议的成功 研究将建立一种新的调控发育突触的机制和信号通路 精致。我们打算为研究小胶质细胞GPR 56的作用奠定基础。 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.

• DOI: 10.1038/s41372-023-01820-3
• 发表时间: 2023-12
• 期刊: JOURNAL OF PERINATOLOGY
• 影响因子: 2.9
• 作者: Jain, Samhita;Oltman, Scott;Rogers, Elizabeth;Ryckman, Kelli;Petersen, Mark;Baer, Rebecca J.;Rand, Larry;Piao, Xianhua;Jelliffe-Pawlowski, Laura
• 通讯作者: Jelliffe-Pawlowski, Laura