Glial Mechanisms Of Developmental Synapse Refinement

摘要 大脑连接决定了我们是谁，但我们对连接机制的理解还处于初级阶段。 突触是神经元之间传递电化学信号的结构单位，构成了大脑的基础 神经网络和突触连接的特殊性决定了大脑的功能。在发育过程中，紧张的人 系统获取过多的突触，经过精细化，以优化信噪比。 发育中的大脑连接部分是通过突触修剪来改进的，这消除了弱突触 允许加强那些保留的人。突触的形成和消除也在成熟期坚持 神经系统通过经验依赖的结构突触可塑性，这是学习的基础。 因此，突触的形成和修剪不仅在发育过程中塑造神经回路方面至关重要 但也在调节突触的可塑性，以回应经验和记忆。突触修剪中的缺陷 和维护被认为与神经发育障碍和神经退化有关。虽然 突触在功能上连接神经元，小胶质细胞和星形胶质细胞等神经胶质支持细胞执行 突触修剪的过程。例如，小胶质细胞补体和Fractalkine的基因操作 小鼠的受体通路已经确凿地证明它们参与了突触修剪。塔姆斯，一位 三个相关受体家族对星形细胞(但显然不是小胶质细胞)突触修剪很重要。 然而，参与这一过程的所有分子成分的光谱仍有待定义。GPR56是 一种黏附-gpr家族的成员，在啮齿动物和人类之间保守。我们未出版的 初步研究表明(1)从小胶质细胞中删除小胶质细胞Gpr56会导致显著的 背外侧膝状神经节(DLGN)视网膜神经支配增加；(2)GPR56结合两者 磷脂酰丝氨酸(PtdSer)和Gas6的GLA结构域；以及(3)缺失Gas6导致显著的 DLGN内突触密度降低。受体与PtdSer和PtdSer的相互作用需要接头蛋白 Gas6就是这样一个适配器。然而，受体的三倍缺失导致了与 Gas6淘汰赛。因此，我们认为Gas6不是通过星形胶质细胞中的受体发挥作用的。 中介突触修剪。相反，将我们的初步数据和其他人公布的结果结合在一起，我们 假设GPR56通过与PtdSer结合来调节小胶质细胞介导的发育性突触细化 Gas6通过竞争GPR56来调节小胶质细胞GPR56介导的突触修剪的程度。 PtdSer交互。我们目前的建议旨在使用遗传模型来检验这一假设， 电生理分析，以及生化和细胞分析。建议的成功 研究将建立一种调节发育突触的新机制和信号通路 精致。我们打算为研究小胶质细胞GPR56在脑内的作用(S)奠定基础。 神经发育障碍及其在神经变性中的潜在作用。

Abstract Brain wiring makes us who we are, but our understanding of the wiring mechanism is still in its infancy. Synapses, the structural units for transmitting electrochemical signals between neurons, form the basis of brain wiring and the specificity of synaptic connections determines brain function. During development, the nervous system acquires an excess of synapses that undergoes refinement, to optimize the signal-to-noise ratio. Developmental brain wiring is refined in part through synaptic pruning, which eliminates weak synapses allowing for strengthening of those retained. Synapse formation and elimination also persist in the mature nervous system through experience-dependent structural synaptic plasticity, which is the basis of learning. Therefore, synaptic formation and pruning are crucial not only in shaping neural circuits during development but also in regulating synaptic plasticity in response to experience and memory. Defects in synaptic pruning and maintenance have been implicated in neurodevelopmental disorders and neurodegeneration. Although synapses functionally connect neurons, the glial support cells such as microglia and astrocytes carry out the process of synapse pruning. For example, genetic manipulation of microglial complement and fractalkine receptor pathways in mice has conclusively demonstrated their involvement in synapse pruning. TAMs, a family of three related receptors, are important for astrocytic (but apparently not microglial) synaptic pruning. However, the full spectrum of molecular components involved in this process remains to be defined. GPR56 is a member of the adhesion-GPCR family, conserved between rodents and humans. Our unpublished preliminary studies showed (1) deleting microglial Gpr56 from mouse microglia leads to a significantly increased retinal innervation in dorsal lateral geniculate ganglion (dLGN); (2) GPR56 binds both phosphatidylserine (PtdSer) and the Gla domain of GAS6; and (3) deleting Gas6 leads to a significantly reduced synaptic density in dLGN. TAM receptors require adaptor protein for their interaction with PtdSer and GAS6 is one such adaptor. However, triple deletion of TAM receptors leads to an opposite phenotype from Gas6 knockout. Therefore, we argue that GAS6 does not function through TAM receptors in astrocyte- mediated synaptic pruning. Instead, taking together our preliminary data and others' published results, we hypothesize that GPR56 regulates microglia-mediated developmental synapse refinement by binding to PtdSer and that GAS6 modulates the degree of microglial GPR56 mediated synaptic pruning by competing GPR56- PtdSer interaction. Our present proposal is designed to test this hypothesis using genetic models, electrophysiological analysis, as well as biochemical and cellular assays. The success of the proposed research will establish a novel mechanism and signaling pathway in regulating developmental synapse refinement. We intend to lay the foundation to investigate the role(s) of microglial GPR56 in neurodevelopmental disorders as well as its potential role in neurodegeneration.