# Long-Lived Synaptic Proteins

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $581,540

## Abstract

PROJECT SUMMARY
Memories can last the entire lifetime of an organism. Dynamic communication among billions of neurons at
synapses underlies information processing and enables the coding and storage of memory. Changes in
synapse strength and structure through synaptic plasticity are widely speculated as the cellular basis of
memory formation and storage. Studies have identified cellular signaling events and molecular rearrangements
underlying the initiation of synaptic plasticity. However, considerably less is known regarding the molecular
basis enabling synaptic strength and memories to persist for extended periods of time. While initial synaptic
plasticity and long-term memory coding requires protein synthesis, following a period of consolidation, memory
storage becomes independent of protein synthesis or neural activity, suggesting that the memory is stored in a
remarkably stable molecular entity. During this time, however, most of the individual proteins that are known to
make up the synapse will turnover, being degraded and replaced within hours to a few days. Therefore the
question remains as to what physical substrates underlie the persistence of long-lasting memories. One
possibility is that exceptionally long-lived proteins (LLPs)
reside in synapses and act as molecular anchors to
maintain the synaptic strength or a network property that defines a given memory.
While previous studies have
demonstrated the existence of LLPs in the central nervous system, particularly in the nuclei of non-dividing
cells, no studies to date have addressed whether such proteins exist at synapses and contribute to the
establishment and maintenance of long-term memories. To investigate this hypothesis we designed an
unbiased, proteomics-based approach to identify LLPs resident in synapses and characterize their neuronal
function. Stable isotope metabolic pulse-chase labeling will be used both in vivo and in vitro to measure the
half-lives of the neuronal and synaptic proteomes. These experiments will further be combined with behavioral
and pharmacological manipulations to examine how memory formation and neuronal activity influence protein
turnover. Identified candidate proteins will be characterized using biochemical, cell-biological,
electrophysiological, imaging and behavioral methodologies to determine how these LLPs contribute to
synaptic/neuronal function and memory. Within the metabolically active environment of the cell it is known that
proteins can undergo oxidative damage. Such damage to LLPs could be a source of vulnerability that may
contribute to functional decline during aging. The experiments described in this proposal will significantly
contribute to our understanding of LLP functions in the brain and their potential role in for memory formation,
long-term storage and age-related cognitive decline.

## Key facts

- **NIH application ID:** 9894864
- **Project number:** 5R01MH112152-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Richard L Huganir
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $581,540
- **Award type:** 5
- **Project period:** 2017-04-05 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894864

## Citation

> US National Institutes of Health, RePORTER application 9894864, Long-Lived Synaptic Proteins (5R01MH112152-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894864. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*