A Novel Presynaptic Role for MHCI in Regulating Cortical Synapse Formation

项目摘要 多年来，研究人员已经观察到免疫系统和神经系统之间相互作用的证据。 系统，但免疫分子在没有疾病的情况下在大脑中发挥非免疫作用的想法， 直到最近才引起人们的注意，这在很大程度上是由于主要组织相容性复合体I的研究 （MHCI）分子。在中枢神经系统中，MHCI在神经元和神经胶质细胞中表达，并调节 发育的许多方面，包括活动依赖性突触细化，突触和稳态 可塑性MHCI还涉及介导广泛的遗传和环境风险因素。 包括自闭症和精神分裂症在内的一系列脑部疾病。除了其在以下方面的作用外， 在可塑性和疾病方面，麦卡利斯特实验室最近证明，神经元上的MHCI分子 负调节皮层神经元连接的建立和功能。MHCI在 突触后细胞显然介导了这种效应，但MHCI也存在于轴突和突触前细胞中。 值得注意是，到目前为止，还没有关于MHCI在这些突触前神经元中的任何功能的报道。 隔间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 负调节它们在目标上形成的突触数量。我论文的中心目标是 确定是否，以及如何，MHCI分子在突触前皮层神经元调节密度， 在目标上形成突触在目标1中，我将确定特定类型的MHCI分子是否 突触前神经元中的H2-Kb和H2-Db负调节突触的密度和动力学， 在皮层培养物中，神经元与它们的目标一起形成。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，以便开始确定MHCI如何在突触前 神经元负调节突触发育。在目标2中，我将确定活动是否调节 神经元突触的密度和动力学，以及神经元突触的突触前效应是否 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： 在早期发育的神经网络中突触形成和消除的蛋白质动力学， 将揭示新的细胞机制介导的影响MHCI在神经发育，包括第一个 突触前MHCI在调节突触形成中的作用。我的研究结果可能因此提供洞察力如何 未来可以开发新的治疗方法来改变大脑中的MHCI信号，以改善神经系统疾病。 基于免疫的疾病。这些发现，连同新的技术和职业技能，我将学习 通过我的培训计划，将使我在未来的神经免疫学事业中取得成功 research.

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.