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 小胶质细胞是来自卵黄囊祖细胞的脑巨噬细胞，具有经典的分配作用， 免疫监视和对损伤或疾病状态的反应。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景观，执行活动，如雕刻和提炼的 在没有外部刺激或疾病的情况下，神经元回路。因此，了解小胶质细胞的作用- 精神健康中的神经元相互作用是一个积极感兴趣的领域。离子化钙结合衔接分子1（Iba 1 a.k.a. AIF 1）是在小胶质细胞中表达的高度保守的蛋白质。Iba 1已被广泛用作 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然未知。在初步研究中， 在Iba 1功能全面缺陷的小鼠中，我们发现这种蛋白质对于小胶质细胞活性是必需的， 通过小胶质细胞分支的减少和几种小胶质细胞的总脑表达的改变来证明， 富含在突触功能和行为中起作用的蛋白质。此外，Iba 1的损失减少了 发育兴奋性突触强度和突触数量增加，但兴奋抑制比增加 涉及海马CA 1区的锥体神经元。这些发育缺陷与以下缺陷相关： 成年Iba 1缺陷小鼠的社会互动。我们假设小胶质细胞Iba 1具有重要的突触功能， 在出生后的发育过程中重塑功能，这反过来又塑造了成年人的行为。因为，Iba 1也是 在CNS相关巨噬细胞、循环单核细胞和外周组织巨噬细胞中表达， 目前尚不清楚Iba 1在小胶质细胞中的特异性功能是否有助于突触中的上述效应， 生理学、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 操纵小胶质细胞活性的iba 1功能丧失模型。我们的两个目标依次涉及神经生理学 和行为后果的Iba 1损失从小胶质细胞在一个关键的发展窗口，并 了解Iba 1在调节小胶质细胞和突触基因表达中的作用， 突触重塑和行为的改变拟议的工作将突出突触的重要性， 小胶质细胞内在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 有助于改善发育中的大脑中的神经元回路，因此可以为 小胶质细胞的治疗靶向，以推进神经发育和神经精神疾病的治疗。