# Investigating the mechanisms of Arc-dependent synaptic plasticity

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

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.

## Key facts

- **NIH application ID:** 10171420
- **Project number:** 5R01MH112766-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jason D Shepherd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2017-06-05 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171420

## Citation

> US National Institutes of Health, RePORTER application 10171420, Investigating the mechanisms of Arc-dependent synaptic plasticity (5R01MH112766-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10171420. Licensed CC0.

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