Investigating the mechanisms of Arc-dependent synaptic plasticity

本提案的首要目标是表征介导贩运的蛋白质机制

The overarching goal of this proposal is to characterize the protein machinery that mediates trafficking of postsynaptic membrane proteins critical for synaptic plasticity. Endo- and exocytosis of membrane proteins are critical trafficking steps in all cells, but are especially dynamic and finely tuned in neurons. Unlike presynaptic endocytosis and synaptic vesicle recycling, the precise molecular processes that underlie postsynaptic trafficking still remain poorly defined. Little is known about how specific receptors are removed from the protein scaffolding complex at the postsynaptic density (PSD) or the functional role of protein-protein interactions within the PSD during synaptic plasticity. Our previous work identified the immediate early gene Arc as a critical mediator of memory storage in the brain and showed that Arc regulates AMPA-type glutamate receptor trafficking. We conducted unbiased proteomic screens and discovered novel Arc interacting proteins. Based on these screens, we hypothesize that Arc acts as a novel postsynaptic clathrin adaptor protein. Based on this hypothesis, we will test whether Arc binds lipids, recruits cargo to endosomes (e.g. AMPARs) and interacts with PSD proteins to release receptors from their scaffolding within the PSD. To study protein trafficking within nanodomains of synapses we have developed a novel live super-resolution light microscopy approach. This study will provide mechanistic insight into how Arc mediates multiple forms of synaptic plasticity and also broadly elucidates the protein machinery that is involved in postsynaptic trafficking of membrane proteins at excitatory synapses. Arc lies at a critical nexus as a critical synaptic effector protein and has been implicated in neurological and psychiatric disorders in human patients. Thus, this work will also shed light on synaptic dysfunction associated with neurological diseases.