# Local mRNA degradation in GluR1 signaling, synaptic plasticity, and cognitive function

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $423,750

## Abstract

PROJECT SUMMARY
A major regulator of synaptic function is local protein synthesis. Deep RNA sequencing has revealed that there
are thousands of dendritically localized mRNAs. Local translation of selected mRNAs in dendrites provides a
fast, adaptive mechanism for the experience-dependent formation of new synapses or the stability of pre-
existing connections. This plasticity underlies changes in neuronal network dynamics and is therefore thought
to be the foundation of learning and memory. Altered protein synthesis and synaptic plasticity are associated
with a variety of neurodevelopmental disorders. However, the pathways that regulate the dendritic proteome
are not well understood.
Protein synthesis in dendrites requires precise regulation of local mRNA stability and translation. A great
amount of prior research has addressed the pathways that regulate translational derepression in dendrites.
However, the mechanisms that control mRNA levels during synaptic function have not been demonstrated. We
have recently shown that intra-axonal translation coupled to the mRNA-degradation pathway `Nonsense
Mediated mRNA Decay' (NMD) controls a switch in receptor expression and thereby regulates axon guidance;
indicating that mRNA turnover is a key player in local protein synthesis. Currently, it is not known whether
mRNA stability in dendrites contribute to the regulation of synaptic plasticity.
The goal of this application is to understand the contribution of intra-dendritic translation coupled to mRNA-
degradation pathway NMD to synaptic plasticity and cognitive performance. The synaptic plasticity protein Arc
is a known target of NMD-mediated mRNA degradation, serving to limit the amount of Arc in dendrites. We
have found that, in addition to Arc, NMD limits the amount of various other proteins involved in GluR1
regulation, which is essential for modulation of synaptic strength. Based on the published literature and our
preliminary studies, we hypothesize that local NMD is as essential for synaptic function as it is for axon
guidance. To test this hypothesis, we propose to determine whether NMD: 1) locally functions in dendrites; 2)
promotes synaptic strength by restricting either internalization or translational repression of GluR1; 3) plays a
role in different forms of synaptic plasticity (e.g. LTP and LTD); 4) is required for learning and memory. We will
use a combination of techniques including a novel microfluidic device to uniquely study synaptic events, an
inducible-genetic mouse model, electrophysiology and behavioral assays. Although NMD is the only RNA
regulatory pathway linked to numerous neurocognitive disorders, it represents a relatively unexplored
mechanism for regulating synaptic function. The successful completion of this research will provide a coherent
view of local proteome dynamics in synaptic plasticity and might be valuable for providing new insights into the
mechanisms of synaptic dysfunction and neurocognitive diseases.

## Key facts

- **NIH application ID:** 10055968
- **Project number:** 5R01MH114888-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Dilek Colak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2018-02-06 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055968

## Citation

> US National Institutes of Health, RePORTER application 10055968, Local mRNA degradation in GluR1 signaling, synaptic plasticity, and cognitive function (5R01MH114888-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10055968. Licensed CC0.

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