Microglia-neuron interactions Roles for microglial Iba1

小胶质细胞-神经元相互作用 小胶质细胞 Iba1 的作用

• 批准号: 10310518
• 负责人: PABLO E CASTILLO
• 金额: $ 12.84万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310518
• 关键词: Actins; Acute; Adaptor Signaling Protein; Address; Adolescent; Adult; Affect; Alleles; Area; Behavior; Behavioral; Binding; Biochemical; Bipolar Disorder; Brain; Cell Surface Proteins; Cell Surface Receptors; Cells; Cytoskeleton; Dendritic Spines; Development; Disease; Electrophysiology (science); Excitatory Synapse; Exhibits; FOXG1B gene; Functional disorder; Gene Expression; Generations; Genes; Hippocampus (Brain); Image; Immune response; Immunologic Surveillance; Inflammatory; Inhibitory Synapse; Interleukin-10; Interleukin-6; Ions; Knockout Mice; Knowledge; Lead; Link; Macrophage-1 Antigen; Mass Spectrum Analysis; Measures; Medicine; Mental Health; Microglia; Modeling; Mus; Neurodevelopmental Disorder; Neurons; Neurosciences; Peripheral; Phagocytosis; Phenotype; Physiology; Proteins; Proteome; Psychoses; Regulation; Research; Role; Schizophrenia; Shapes; Slice; Social Behavior; Social Interaction; Stimulus; Structure; Synapses; Synaptic Transmission; TREM2 gene; Testing; Therapeutic; Tissues; Transcript; Work; Yolk Sac; allograft inflammatory factor-1; autism spectrum disorder; behavior test; brain cell; brain tissue; cell motility; cell type; cognitive function; cytokine; density; hippocampal pyramidal neuron; improved; insight; interest; loss of function; mRNA sequencing; macrophage; monocyte; neural circuit; neuronal circuitry; neurophysiology; neuropsychiatric disorder; neuropsychiatry; neurotransmitter release; novel therapeutic intervention; postnatal; postnatal development; progenitor; programs; response to injury; stem; synaptic function; therapeutic target; transmission process

ABSTRACT Microglia are brain macrophages derived from yolk-sac progenitors, with classically assigned roles that center on immune surveillance and response to an injury or a disease state. Recent views, however, have moved microglia into the landscape of normal brain function, performing activities such as sculpting and refining of neuronal circuitry in the absence of external stimuli or disease. Thus, understanding the contribution of microglia- neuron interactions in mental health is an area of active interest. Ionized Ca2+-binding adapter molecule 1 (Iba1 a.k.a. AIF1) is a highly conserved protein expressed in microglia. Iba1 has been used widely as a marker of microglia, but its contributions to microglial and brain functions remain largely unknown. In preliminary studies of mice globally deficient for Iba1 function, we have found that this protein is essential for microglial activity, evidenced by reductions in microglial branching and alterations in the total brain expression of several microglial- enriched proteins that have roles in synaptic function and behavior. Furthermore, loss of Iba1 reduces developmental excitatory synaptic strength and synapse numbers but enhances excitation-inhibition ratio involving the pyramidal neurons of CA1 hippocampus. These developmental deficits correlate with a deficit in social interaction in adult Iba1-deficient mice. We hypothesize that microglial Iba1 has important synaptic remodeling functions during postnatal development, which in turn shapes adult behavior. Since, Iba1 is also expressed in CNS-associated macrophages, circulating monocytes and peripheral tissue macrophages, it is unclear whether Iba1 function specifically in microglia contributed to the aforementioned effects in synaptic physiology, gene expression and behavior. To test these ideas, we will take advantage of our unique conditional Iba1 loss-of-function model to manipulate microglial activity. Our two aims address in turn the neurophysiological and behavioral consequences of Iba1 loss from microglial cells during a critical developmental window, and to understand the contributions of Iba1 in the modulation of microglial and synaptic gene expression that underlie an altered synaptic remodeling and behavior. The proposed work will highlight the importance of synaptic developmental functions regulated by a microglia-intrinsic protein and further attempt to showcase the impact of such regulation on behavior. Knowledge gained from this study will advance our understanding of how microglia contribute to the refinement of neuronal circuitry in a developing brain, and thus may provide a rationale for therapeutic targeting of microglia, to advance treatment of neurodevelopmental and neuropsychiatric disorders.

摘要 小胶质细胞是由卵黄囊前体细胞衍生而来的脑巨噬细胞，其典型的角色是 关于免疫监测和对伤害或疾病状态的反应。然而，最近的观点发生了变化 小胶质细胞进入正常大脑功能的版图，执行诸如雕刻和提炼 在没有外界刺激或疾病的情况下的神经元回路。因此，了解小胶质细胞的贡献- 心理健康中的神经元相互作用是一个活跃的研究领域。离子钙结合接头分子1(IBA1) 又名。AIF1)是一种在小胶质细胞中表达的高度保守的蛋白质。Iba1已被广泛用作一种标记 小胶质细胞，但其对小胶质细胞和脑功能的贡献在很大程度上仍不清楚。在对…的初步研究中 对于缺乏Iba1功能的小鼠，我们发现这种蛋白对小胶质细胞的活动是必不可少的， 小胶质细胞分支减少和几种小胶质细胞总表达的变化- 富含在突触功能和行为中起作用的蛋白质。此外，Iba1的损失减少了 发育性兴奋性突触强度和突触数目，但增强兴奋-抑制比 累及CA1区锥体神经元。这些发育缺陷与 成年Iba1基因缺陷小鼠的社会互动。我们假设小胶质细胞Iba1具有重要的突触 重塑在出生后发育过程中起作用，进而塑造成年人的行为。因为，IBA1也是 在中枢神经系统相关巨噬细胞、循环单核细胞和外周组织巨噬细胞中表达 尚不清楚IBA1在小胶质细胞中的功能是否参与了突触的上述效应 生理、基因表达和行为。为了测试这些想法，我们将利用我们独特的条件 IBA1功能丧失模型来操纵小胶质细胞的活动。我们的两个目标依次解决了神经生理学 以及在关键发育窗口期间小胶质细胞Iba1缺失的行为后果，以及 了解Iba1在调节小胶质细胞和突触基因表达中的作用 改变了突触的重塑和行为。拟议的工作将突出突触的重要性 由小胶质细胞固有蛋白调节的发育功能，并进一步试图展示 这样的行为规范。从这项研究中获得的知识将促进我们对小胶质细胞如何 有助于完善发育中的大脑中的神经元电路，因此可能为 治疗靶向小胶质细胞，以促进神经发育和神经精神疾病的治疗。