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

基本信息

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
项目类别：
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

项目摘要

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卵黄囊祖细胞的脑巨噬细胞，其经典分配的作用是关于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，执行诸如雕刻和精炼之类的活动在没有外部刺激或疾病的情况下，神经元回路。因此，了解小胶质细胞的贡献心理健康中的神经元相互作用是一个令人感兴趣的领域。离子化 Ca2+ 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已被广泛用作小胶质细胞，但其对小胶质细胞和大脑功能的贡献仍然很大程度上未知。在初步研究中小鼠整体缺乏 Iba1 功能，我们发现这种蛋白质对于小胶质细胞活性至关重要，小胶质细胞分支的减少和几种小胶质细胞总脑表达的改变证明了这一点丰富的蛋白质在突触功能和行为中发挥作用。此外，Iba1 的损失减少了发育兴奋性突触强度和突触数量，但提高兴奋抑制比涉及海马 CA1 锥体神经元。这些发育缺陷与以下方面的缺陷相关：成年 Iba1 缺陷小鼠的社交互动。我们假设小胶质细胞 Iba1 具有重要的突触功能在出生后发育过程中重塑功能，进而塑造成人行为。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 在小胶质细胞中的特异功能是否导致了上述对突触的影响生理学、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用于操纵小胶质细胞活动的 Iba1 功能丧失模型。我们的两个目标依次解决神经生理学问题以及在关键发育窗口期间小胶质细胞 Iba1 丢失的行为后果，以及了解 Iba1 在调节小胶质细胞和突触基因表达方面的贡献突触重塑和行为的改变。拟议的工作将强调突触的重要性由小胶质细胞固有蛋白调节的发育功能，并进一步尝试展示这样的行为规范。从这项研究中获得的知识将加深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回路，因此可能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。