A Novel Presynaptic Role for MHCI in Regulating Cortical Synapse Formation

项目摘要 多年来，研究人员一直观察到免疫系统和神经质之间存在相互作用的证据。 但免疫分子在没有疾病的情况下在大脑中扮演非免疫角色的想法 直到最近才得到关注，这在很大程度上是由于专注于主要组织相容性复合体I的工作 (MHCI)分子。在中枢神经系统中，MHCI在神经元和胶质细胞中表达，并调节 发育的许多方面，包括依赖活动的突触细化，以及突触和内稳态 可塑性。MHCI也被牵连到调节广泛的遗传和环境风险因素 一系列脑部疾病，包括自闭症和精神分裂症。除了它在 可塑性和疾病，麦卡利斯特实验室最近证明了神经元上的MHCI分子 负向调节皮层神经元连接的建立和功能。MHCI在 突触后细胞明显地介导了这种影响，但MHCI也存在于轴突和突触前 而且值得注意的是，到目前为止还没有关于MHCI在这些突触前的任何功能的报道 车厢。使用一种新的共培养系统，我发现突触前神经元中的MHCI水平 负向调节它们在靶子上形成的突触数量。我论文的中心目标是 确定突触前皮质神经元中的MHCI分子是否以及如何调节 突触形成在它们的目标上。在目标1中，我将确定特定类型的MHCI分子 突触前神经元中的(H2-KB和H2-DB)负向调节突触的密度和动力学 在皮质培养中，神经元与它们的靶细胞一起形成。然后，我将使用一种新颖的、创新的长期成像分析 测量MHCI对突触动力学的影响，以开始确定MHCI如何在突触前 神经元负向调节突触发育。在目标2中，我将确定活动是否调节 细胞在其靶点上形成的突触的密度和动力学，以及突触前效应是否 MHCI对突触密度的影响具有活性依赖性。该项目的结果将提供有关以下方面的新信息 早期发育的神经网络中突触形成和消除的蛋白质动力学 将揭示介导MHCI在神经发育中的作用的新的细胞机制，包括第一 突触前MHCI在调节突触形成中的作用。因此，我的发现可能会为我们提供关于 未来可以开发新的疗法来改变大脑中的MHCI信号，以改善神经- 免疫性疾病。这些发现，以及我将学到的新技术和职业技能 通过我的培训计划，将为我未来在神经免疫学领域的成功职业生涯做好最好的准备 研究。

Project Summary For years, researchers have observed evidence of cross–talk between the immune system and the nervous system, but the idea that immune molecules play non-immune roles in the brain in the absence of disease has only recently gained attention, due in large part to work focusing on the major histocompatibility complex I (MHCI) molecules. In the central nervous system, MHCI is expressed in neurons and glial cells and regulates many aspects of development, including activity-dependent synaptic refinement, and synaptic and homeostatic plasticity. MHCI has also been implicated in mediating both genetic and environmental risk factors of a wide range of brain diseases, including autism and schizophrenia. In addition to its well-documented roles in plasticity and disease, the McAllister laboratory recently demonstrated that MHCI molecules on neurons negatively regulate the establishment and function of connections onto cortical neurons. MHCI in the postsynaptic cell clearly mediates some of this effect, but MHCI is also present in axons and in the presynaptic terminal and remarkably, there are no reports to date of any function for MHCI in these presynaptic compartments. Using a novel co-culture system, I have discovered that MHCI levels in presynaptic neurons negatively regulate the number of synapses they form onto their targets. The central goal of my thesis is to determine whether, and how, MHCI molecules in presynaptic cortical neurons regulate the density of synapses formed onto their targets. In Aim 1, I will determine whether specific types of MHCI molecules (H2-Kb and H2-Db) in presynaptic neurons negatively regulate the density and dynamics of synapses those neurons form with their targets in cortical cultures. Then, I will use a novel, innovative long-term imaging assay to measure the effect of MHCI on synapse dynamics in order to start to determine how MHCI in presynaptic neurons negatively regulates synapse development. In Aim 2, I will determine whether activity regulates the density and dynamics of synapses a cell makes onto its targets, as well as whether the presynaptic effects of MHCI on synapse density are activity-dependent. Results from this project will provide new information about the protein dynamics underlying synapse formation and elimination in early developing neural networks and will reveal novel cellular mechanisms mediating the effects of MHCI in neural development, including the first role for presynaptic MHCI In regulating synapse formation. My findings may thereby provide insight into how novel therapies could be developed to alter MHCI signaling in the brain in the future to ameliorate neuro- immune-based disorders. These discoveries, together with the new techniques and career skills I will learn through my training plan, will position me optimally for a successful future career in neuroimmunology research.