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: 10157121
• 负责人: PABLO E CASTILLO
• 金额: $ 24.4万
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157121
• 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.

抽象的 小胶质细胞是源自蛋黄 - 核祖细胞的脑巨噬细胞，具有经典分配的角色 关于免疫监测和对伤害或疾病状态的反应。然而，最近的观点已经移动 小胶质细胞进入正常脑功能的景观，进行雕刻和精炼等活动 在没有外部刺激或疾病的情况下，神经元电路。因此，了解小胶质细胞的贡献 心理健康方面的神经元相互作用是一个积极关注的领域。电离Ca2+结合衔接子分子1（IBA1 又称AIF1）是一种在小胶质细胞中表达的高度保守蛋白。 IBA1已被广泛用作标记 小胶质细胞，但其对小胶质细胞和大脑功能的贡献在很大程度上未知。在初步研究中 在全球缺乏IBA1功能的小鼠中，我们发现该蛋白对于小胶质活性至关重要， 小胶质分支的减少和几个小胶质细胞总脑表达的改变证明了 在突触功能和行为中具有作用的富集蛋白质。此外，IBA1的损失减少了 发育兴奋性突触强度和突触数量，但增强了激发抑制比 涉及CA1海马的锥体神经元。这些发育缺陷与赤字相关 成年IBA1缺陷小鼠的社交互动。我们假设小胶质iba1具有重要的突触 产后发育过程中的重塑功能又塑造了成人行为。从那以后，iba1也是 在CNS相关的巨噬细胞，循环单核细胞和外周组织巨噬细胞中表达，它是 尚不清楚IBA1在小胶质细胞中是否特别有助于上述突触效应 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功能丧失模型操纵小胶质细胞活性。我们的两个目标依次介绍了神经生理学 在关键的发育窗口中，小胶质细胞损失IBA1损失的行为后果， 了解IBA1在小胶质细胞和突触基因表达的调节中的贡献 突触重塑和行为改变。拟议的工作将突出突触的重要性 由小胶质细胞蛋白调节的发育功能，并进一步尝试展示 这种行为的调节。从这项研究中获得的知识将促进我们对小胶质细胞的理解 有助于神经元电路在发育中的大脑中的细化，因此可以为 小胶质细胞的治疗靶向，以促进神经发育和神经精神疾病的治疗。