# Analysis of synaptic protein dynamics

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $412,573

## Abstract

Project Summary
Synapses are fundamental to nervous system function and information processing in the normal and
pathological brain. They are highly dynamic structures capable of supporting high firing rates and displaying a
broad range of plasticity. A detailed picture of the molecular interactions occurring within a synapse is required
to understand how synaptic protein dynamics ultimately shape activity in the nervous system in health and
disease.
In this proposal, we will investigate Munc13 and complexin (CPX), both highly conserved molecules that are
crucial for proper synaptic function. Mice lacking complexin die at birth, and loss of a single isoform is
associated with profound locomotor, sensory, and behavioral deficits. A human Cpx1 point mutation is
associated with severe intellectual disability and seizures, and CPX expression is altered in a host of
psychiatric and neurodegenerative diseases including Huntington’s, Parkinson’s, and Alzheimer’s disease.
Although it is well-established that complexin plays a major role in synaptic function, its mode of action is
controversial: there is evidence for both facilitatory and inhibitory roles of this protein in the regulation of
synaptic transmission. Munc13 is a large synaptic hub protein that coordinates several proteins involved in
synaptic vesicle fusion, and human mutations are associated with ALS, fatal myasthenia, microcephaly, and
severe autism. We propose to study the molecular mechanisms underlying Munc13 and CPX function at the
synapse using a unique and powerful combination of in vivo and in vitro approaches including physiology,
quantitative imaging, behavioral assays, genetics, and protein/lipid biochemistry.
We have developed innovative methods of investigating protein interactions in vivo by monitoring the dynamics
of proteins exchanging between neighboring synapses using photoactivatable GFP. We will deploy these
methods in C. elegans as a model system in which to study the protein interactions of CPX as well as domains
of Munc13 and their binding partners in a functional synapse. By mutating either the pGFP-tagged protein or
its binding partners, we have established that affinity changes lead to mobility changes. We will also elucidate
the structure of CPX and Munc13 protein domains that mediate critical membrane interactions using a
combination of biochemical and spectroscopic techniques. Detailed structure-function analyses will be
conducted on a domain of Munc13 recently discovered in our lab.
The experiments proposed here will provide new insights into the mechanisms that control neurotransmitter
release, its modulation, and use-dependent plasticity in the brain.

## Key facts

- **NIH application ID:** 10143323
- **Project number:** 5R01NS116747-11
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jeremy Samuel Dittman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,573
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143323

## Citation

> US National Institutes of Health, RePORTER application 10143323, Analysis of synaptic protein dynamics (5R01NS116747-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143323. Licensed CC0.

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