Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling

小胶质细胞-星形胶质细胞串扰调节突触重塑

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要该提案的目的是确定小胶质细胞和星形胶质细胞如何进行改造突触。数万亿个突触形成了大脑中高度精确的电路图。这些地图是形状的，通过感官体验（视觉，触摸等）维护，包括消除较不活跃的突触和F 维护和加强其他突触。尽管进行了50多年的研究，但基础活动决定去除某些突触而不是其他的机制仍然是一个悬而未决的问题。我们最初发现的是，小胶质细胞是一种常驻的中枢神经系统（CNS）巨噬细胞，engulf和消除发育中的视网膜生成和枪管皮层电路中的活性突触较少。在最后的资金中循环，我们表明在新生儿的鼻子一侧清除晶须会导致小胶质吞噬并消除相应桶皮层中的丘脑皮质（TC）突触。与视网膜生成不同电路，这不是通过完成的监管。相反，小胶质细胞未能吞噬并消除了TC突触缺乏神经元分裂（CX3CL1）的小鼠 - 小胶质细胞分子受体（CX3CR1）信号传导。这项工作确定潜水员的神经胶质机制调节活动依赖性突触重塑并打开了新的问题：成人大脑中的小胶质细胞重塑？有证据表明星形胶质细胞也吞噬了突触在其他中枢神经系统电路中，星形胶质细胞是否还参与桶皮层突触重塑？如果是这样，他们与小胶质细胞沟通以调节这一过程？我们的新初步数据表明，星形胶质细胞没有响应新生儿的晶须去除晶须，而是减少了与突触的接触以CX3CL1依赖性方式。另外，小胶质细胞不再吞噬晶须之后的突触年龄较大的动物，与星形胶质细胞突触升高的伴随。细胞特异性rnaseq以下晶须的进一步揭示了规范的Wnt信号传导作为一种假定的机制，小胶质细胞信号向星形胶质细胞调节突触。现在，我们提出了一个小胶质细胞调节的新型模型在活动中突触的星形胶质细胞和CX3CL1-CX3CR1-WNT依赖性方式。反过来，小胶质细胞获得吞噬并删除TC突触。现在我们将利用枪管皮质的力量具有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突触吞噬和星形胶质细胞突触导致（AIM 1）。 2）确定是否突触的星形胶质细胞影响会影响小胶质细胞依赖性突触重塑（AIM 2）。 3）确定如何小胶质细胞调节突触的星形胶质细胞（AIM 3）。答案将解决一些突触的方式当其他人完好无损时，被神经胶质消除了，这是该领域的关键问题，对各种神经发育障碍和神经退行性疾病，突触的潜在变化连接性。