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.

摘要