Defining native glutamate receptor diversity

点击翻译按钮获取中文摘要

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