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.
The overall goal of our research is to understand, at the molecular and cellular level, how information is stored in the brain. This proposal leverages current state-of-the-art imaging techniques to determine the molecular mechanisms of Arc-dependent AMPA-type glutamate receptor trafficking and the role of these processes in synaptic plasticity, the leading cellular models of learning and memory.
| Pastuzyn, Elissa D; Day, Cameron E; Kearns, Rachel B et al. (2018) The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer. Cell 173:275 |
| Pastuzyn, Elissa D; Day, Cameron E; Kearns, Rachel B et al. (2018) The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer. Cell 172:275-288.e18 |
| Shepherd, Jason D (2018) Arc - An endogenous neuronal retrovirus? Semin Cell Dev Biol 77:73-78 |
| Jenks, Kyle R; Kim, Taekeun; Pastuzyn, Elissa D et al. (2017) Arc restores juvenile plasticity in adult mouse visual cortex. Proc Natl Acad Sci U S A 114:9182-9187 |
| Pastuzyn, Elissa D; Shepherd, Jason D (2017) Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome. Front Mol Neurosci 10:234 |
