Defining native glutamate receptor diversity

总结 谷氨酸能突触具有异常多样的蛋白质组，包括1000多个高度保守的 突触蛋白的突变会导致不同的行为后果。知识有限 突触间的分子组织阻碍了我们对突触多样性的理解 有助于大脑功能，并导致通用的，往往无效的，治疗。我们的目标是推进理性 治疗设计，通过定义组织，功能和功能， 精确的突触谷氨酸受体群体的治疗潜力。该项目旨在定义 天然谷氨酸受体复合物的组成和组织， 受体生物学的挑战。我们研究了丘脑中突触的分子组织， 其异常多样的神经递质输入和基因表达以及其参与各种疾病。 我们最近的工作表明谷氨酸N-甲基-D-天冬氨酸受体（NMDAR）家族的关键作用 受体参与丘脑的专门信号处理职责。NMDAR是四聚体， 具有不同功能特性的不同亚基组合，从而具有不同的治疗潜力。 值得注意的是，我们仍然不知道天然脑组织中存在哪些亚基组合。我们假设 NMDAR亚基优先与特定的相关大分子组装在特定的组合中 导致大脑中独特的亚细胞组织的复合体。这项工作利用创新的 包括新的生化策略，超分辨率成像和基因组编辑技术在内的方法， 确定：1）天然NMDAR大分子复合物的不同组成，以及2）NMDAR如何 定位在突触处产生分子多样性。该项目的结果将指导治疗策略 在正在进行的小鼠疾病模型研究中，以及在开发亚型选择性 NMDAR调节剂。此外，这种方法可以应用于许多神经递质受体， 家庭，因此有可能推进许多神经系统疾病的治疗设计。 1

SUMMARY Glutamatergic synapses have an exceptionally diverse proteome consisting of more than 1000 highly conserved proteins, and mutations in synaptic proteins cause varied behavioral consequences. Limited knowledge of molecular organization among glutamatergic synapses hinders our understanding of how synapse diversity contributes to brain function and results in generic, often ineffective, therapies. Our goal is to advance rational therapy design that selectively targets disrupted brain circuits by defining the organization, function, and therapeutic potential of precise synaptic glutamate receptor populations. This project seeks to define the composition and organization of native glutamate receptor complexes by overcoming long-standing technical challenges in receptor biology. We study molecular organization at glutamatergic synapses in the thalamus due to its exceptionally diverse glutamatergic input and gene expression as well as its involvement in varied diseases. Our recent work suggests key roles for the N-methyl-D-aspartate receptor (NMDAR) family of glutamate receptors in the specialized signal processing duties of the thalamus. NMDARs are tetramers that can assemble in various subunit combinations with distinct functional properties, and thus distinct therapeutic potential. Remarkably, we still do not know which subunit combinations exist in native brain tissue. We hypothesize that NMDAR subunits preferentially assemble in particular combinations with specific associated macromolecular complexes that lead to distinct subcellular organization in the brain. The proposed work utilizes innovative approaches including novel biochemical strategies, super-resolution imaging, and genome editing techniques to determine: 1) the diverse composition of native NMDAR macromolecular complexes, and 2) how NMDAR localization generates molecular diversity at synapses. Outcomes of this project will guide treatment strategies in ongoing studies with mouse disease models as well as sustained efforts in developing subtype-selective NMDAR modulators. Moreover, this approach could be applied to a number of neurotransmitter receptor families, and thus has the potential to advance therapy design for many neurological diseases. 1