Microglia function in synaptic plasticity

描述（由申请人提供）：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，具有高度的运动过程，占据不重叠的领土。在生理条件下，小胶质细胞可能监测大脑微环境的损伤信号，参与神经回路的发育和可塑性。病理条件下，小胶质细胞发生一系列形态和功能变化，可能参与组织损伤、吞噬和清除细胞碎片、促炎因子的分泌等。尽管小胶质细胞与中枢神经系统的许多生理和病理过程有关，但其功能的直接证据仍然难以捉摸。由于缺乏在体内特异性干扰小胶质细胞功能的工具，阻碍了对小胶质细胞作用的描述。我最近培养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。这种转基因小鼠系为小胶质细胞的体内操作提供了分子处理，包括删除。通过在活体小鼠中特异性切除小胶质细胞，我将阐明小胶质细胞在动物行为和学习依赖的突触可塑性中的作用。由于活化的小胶质细胞几乎参与了大脑的所有病理状态，因此提出的研究旨在确定其功能

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.