Molecular Architecture and Function of synaptic AMPA receptor complexes - Abstract: Synaptic transmission is a key process for communication between neuronal cells. Despite numerous advances, our understanding of the molecular details of synaptic transmission remains incomplete. Deciphering the molecular details behind synaptic transmission could potentially lead to the development of strategies for treatment of uncurable neurological disorders. In mammalian brain, communication through neurotransmitter glutamate is the most common. From the several types of receptors that are activated by glutamate, AMPARs (α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic receptors) stand out because they interact with numerous regulatory proteins that affect AMPARs function. In the proposed experiments, we aim to uncover mechanistic details of inter-neuronal AMPAR-mediated communication. We present a set of experiments and advancements that will lead to high-resolution 3D structural views of AMPAR-based protein complexes with regulatory proteins in their most physiologically relevant conformation. By leveraging state-of-art custom biochemical, analytical, and biophysical approaches, we will obtain the structure of physiologically relevant synaptic AMPAR complexes with regulatory proteins. Next, we will gain functional insights into how those complexes are responsible for the maintenance of the efficient synaptic transmission. We will validate our findings by a set of biochemical approaches as well as by electrophysiological recordings coupled with in situ cryoelectron tomography (cryo-ET) imaging of the synapses in fresh mouse brain slices. In addition to several technological advancements that are potentially transferable to other transient protein assemblies, our research will exert a major scientific impact on the AMPARs and synaptic transmission fields. With the stellar team of collaborators, our expertise in the relevant fields, carefully designed strategies, and awareness of potential pitfalls, we are highly confident in the success of our studies aimed at understanding of synaptic transmission mechanisms. Ultimately, we aim to utilize obtained structural information for the future structure-based therapeutics design that will combat pathologies linked to altered synaptic transmission.
