Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling

小胶质细胞-星形胶质细胞串扰调节突触重塑

• 批准号: 10614621
• 负责人: Dorothy Patricia Schafer
• 金额: $ 57.97万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614621
• 关键词: Ablation; Adult; Age; Alzheimer' s Disease; Animals; Astrocytes; Brain; CX3CL1 gene; Cauterize; Cells; Central Nervous System; Communication; Complement; Data; Development; Disease; Electron Microscopy; Excision; Face; Fractalkine; Funding; Genetic; Goals; Immune; Left; Lesion; Ligands; Macrophage; Maintenance; Maps; Mediating; Microglia; Microscopy; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neurons; Organism; Predisposition; Process; Receptor Signaling; Research; Schizophrenia; Sensory; Shapes; Side; Signal Transduction; Synapses; Testing; Thinking; Touch sensation; Vibrissae; Vision; WNT Signaling Pathway; Work; barrel cortex; brain cell; cell type; density; experience; fractalkine receptor; genetic approach; neonate; neural; neural circuit; neuroligin 2; neuropsychiatric disorder; neurotransmission; novel; overexpression; prevent; receptor; response; retinogeniculate; tool; transcriptome sequencing

Project Summary The goal of this proposal is to determine how microglia and astrocytes communicate to remodel synapses. Trillions of synapses form highly precise circuit maps in the brain. These maps are shaped and maintained by sensory experience (vision, touch, etc.), including elimination of less active synapses and f maintenance and strengthening of other synapses. Despite over 50 years of research, the underlying mechanisms by which activity dictates removal of some synapses, but not others, remains an open question. We made the initial discovery that microglia, a resident central nervous system (CNS) macrophage, engulf and eliminate less active synapses in the developing retinogeniculate and barrel cortex circuits. In the last funding cycle, we showed that removal of whiskers on one side of the snout in neonates resulted in microglial engulfment and elimination of thalamocortical (TC) synapses in the corresponding barrel cortex. Unlike the retinogeniculate circuit, this was not regulated by complement. Instead, microglia failed to engulf and eliminate TC synapses in mice deficient in neuronal fractalkine (CX3CL1)-to microglial fractalkine receptor (CX3CR1) signaling. This work established that diverse glial mechanisms regulate activity-dependent synapse remodeling and opened up new questions: Do microglia remodel synapses in the adult brain? With evidence that astrocytes also engulf synapses in other CNS circuits, are astrocytes also involved in barrel cortex synapse remodeling? If so, do they communicate with microglia to regulate this process? Our new preliminary data show that astrocytes do not engulf synapses in response to whisker removal in neonates, but rather they reduce their contact with synapses in a CX3CL1-dependent manner. Also, microglia no longer engulf TC synapses following whisker removal in older animals, concomitant with elevated astrocyte synapse ensheathment. Cell-specific RNAseq following whisker removal further reveals canonical Wnt signaling as a putative mechanism by which microglia signal to astrocytes to regulate synapse ensheathment. We now propose a novel model by which microglia regulate astrocyte ensheathment of synapses in an activity and CX3CL1-CX3CR1-Wnt dependent manner. In turn, microglia gain access to engulf and remove TC synapses. We will now leverage the power of the barrel cortex circuit with cell-specific genetic approaches to: 1) Define the developmental window for CX3CL1-CX3CR1- dependent microglial synapse engulfment and astrocyte synapse ensheathment (Aim 1). 2) Determine if astrocyte ensheathment of synapses impacts microglia-dependent synapse remodeling (Aim 2). 3) Identify how microglia regulate astrocyte ensheathment of synapses (Aim 3). Answers will address how some synapses are eliminated by glia while others are left intact—a key open question in the field with implications for a variety of neurodevelopmental disorders and neurodegenerative diseases with underlying changes in synaptic connectivity.

项目概要 该提案的目标是确定小胶质细胞和星形胶质细胞如何通信以进行重塑 突触。数以万亿计的突触在大脑中形成了高度精确的电路图。这些地图的形状和 由感官体验（视觉、触觉等）维持，包括消除不太活跃的突触和 f 维护和加强其他突触。尽管经过 50 多年的研究，其基本原理 活动决定去除某些突触而不是其他突触的机制仍然是一个悬而未决的问题。 我们最初发现小胶质细胞是一种常驻中枢神经系统（CNS）巨噬细胞，吞噬并吞噬 消除发育中的视网膜皮层和桶状皮层回路中不太活跃的突触。在上一次融资中 循环中，我们发现去除新生儿鼻子一侧的胡须会导致小胶质细胞吞噬 并消除相应桶状皮质中的丘脑皮质（TC）突触。与视网膜原化不同 电路，这不受补体调节。相反，小胶质细胞未能吞噬并消除 TC 突触 神经元 fractalkine (CX3CL1) 至小胶质细胞 fractalkine 受体 (CX3CR1) 信号传导缺陷的小鼠。这部作品 确定多种神经胶质机制调节活动依赖性突触重塑，并开辟了新的途径 问题：小胶质细胞会重塑成人大脑中的突触吗？有证据表明星形胶质细胞也吞噬突触 在其他中枢神经系统回路中，星形胶质细胞是否也参与桶状皮层突触重塑？如果是这样，他们是否 与小胶质细胞沟通来调节这个过程？我们新的初步数据表明星形胶质细胞不 吞噬突触是对新生儿胡须去除的反应，但它们减少了与突触的接触 以CX3CL1依赖的方式。此外，在去除晶须后，小胶质细胞不再吞噬 TC 突触。 老年动物，伴有星形胶质细胞突触鞘升高。细胞特异性 RNAseq 如下 晶须去除进一步揭示了典型的 Wnt 信号传导是小胶质细胞向细胞发出信号的一种推定机制。 星形胶质细胞调节突触鞘。我们现在提出了一种小胶质细胞调节的新模型 星形胶质细胞以活性和 CX3CL1-CX3CR1-Wnt 依赖性方式包裹突触。反过来， 小胶质细胞可以吞噬并去除 TC 突触。我们现在将利用桶状皮层的力量 采用细胞特异性遗传方法的电路：1) 定义 CX3CL1-CX3CR1- 的发育窗口 依赖的小胶质细胞突触吞噬和星形胶质细胞突触鞘（目标 1）。 2）确定是否 星形胶质细胞突触鞘影响小胶质细胞依赖性突触重塑（目标 2）。 3）确定如何 小胶质细胞调节突触的星形胶质细胞鞘（目标 3）。答案将解决一些突触的情况 被神经胶质细胞消除，而其他的则完好无损——这是该领域的一个关键的悬而未决的问题，对多种领域都有影响 具有突触潜在变化的神经发育障碍和神经退行性疾病 连接性。