Microglia function in synaptic plasticity

描述(申请人提供)：本提案的目标是确定小胶质细胞在调节大脑结构和功能中的作用。小胶质细胞是中枢神经系统的常驻免疫细胞，显示出占据非重叠区域的高度能动性的突起。在生理条件下，小胶质细胞可以监测大脑微环境中的损伤信号，并参与神经回路的发育和可塑性。在病理条件下，小胶质细胞经历了一系列的形态和功能变化，可能参与控制组织损伤、吞噬和清除细胞碎片，和/或分泌促炎因子。虽然小胶质细胞参与了中枢神经系统的多种生理和病理过程，但对其功能的直接证据仍然很难找到。阻碍描述小胶质细胞作用的努力是缺乏专门干扰体内小胶质细胞功能的工具。我最近培育了一种靶向基因插入的小鼠，允许在表达CX3CR1的小胶质细胞中表达他莫昔芬诱导的Cre重组酶。这一转基因小鼠系为体内操作小胶质细胞包括缺失提供了一个分子手柄。通过专门消融活着的小鼠的小胶质细胞，我将阐明小胶质细胞在正常行为和依赖学习的突触可塑性中的作用。由于激活的小胶质细胞几乎参与了大脑中的每一种病理状态，因此拟议的研究旨在确定 小胶质细胞将为许多神经系统疾病的理解和治疗提供重要的见解。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the role of microglia in regulating the structure and function of the brain. Microglia are the resident immune cells of the central nervous system and display highly motile processes occupying a non-overlapping territory. Under physiological conditions, microglia may monitor the brain's microenvironment for damage signals and participate in the development and plasticity of neural circuits. Under pathological conditions, microglia undergo a series of morphological and functional changes, and may engage in containing tissue damage, phagocytosis and clearance of cellular debris, and/or the secretion of proinflammatory factors. Although microglia have been implicated in a multitude of physiological and pathological processes in the central nervous system, direct evidence of their functions remains elusive. Hampering efforts to delineate the role of microglia is the lack of tools to specifically perturb microglial function in vivo. I have recently generated mice with a targeted gene insertion allowing for the expression of tamoxifen- inducible Cre recombinase in CX3CR1 expressing microglial cells. This transgenic mouse line provides a molecular handle for the in vivo manipulation of microglia including deletion. By specifically ablating microglial cells in living mice, I will elucidate the role of microglia in anmal behavior and learning-dependent synaptic plasticity. As activated microglia are involved in almost every pathological condition in the brain, the proposed studies to identify the functions of microglia will provide important insights for the understanding and treatment of many neurological diseases.