# Characterization of the Drosophila Synaptotagmin Family

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $343,293

## Abstract

The goal of this study is to characterize the molecular mechanisms that detect Ca2+ rises in
synaptic terminals and identify how these components drive synaptic communication between
neurons using the Drosophila model. Research from my lab and others has demonstrated the
importance of the Synaptotagmin (Syt) family of Ca2+ binding proteins in translating synaptic
Ca2+ dynamics into the regulation of neuronal communication. Given mutations in
Synaptotagmins have been found to cause both CNS and neuromuscular disorders in humans,
it is essential to understand how this protein family regulates synaptic communication.
Presynaptically, Ca2+ entry triggers synaptic vesicle (SV) fusion through a synchronous phase
that occurs within milliseconds, and a slower asynchronous phase that can last for hundreds of
milliseconds. Postsynaptic Ca2+ influx also regulates membrane trafficking at synapses to drive
retrograde signaling pathways that link neuronal activity and synaptic growth. In Aim 1, we will
define how Syt1 interfaces with Complexin and the SNARE complex to control whether SVs
fuse synchronously, asynchronously or spontaneously. We will also determine how mutations in
human Syt1 and Syt2 dominantly disrupt SV fusion and lead to neurological disease. In Aim 2,
we will characterize how Syt7, a popular candidate for the asynchronous and short-term
facilitation Ca2+ sensor, regulates SV release. In particular, we will test if Syt7 negatively
regulates release by inhibiting fusogenicity of SVs in the reserve pool and activating Ca2+-dependent recycling routes that decrease SV replenishment rate at AZs. In Aim 3, we will
analyze how the Syt4 Ca2+ sensor interfaces with postsynaptic SNAREs to mediate retrograde
signaling and control synaptic plasticity. In addition, we will identify new components of
retrograde signaling using genetic screens to assay for defects in postsynaptic membrane
trafficking. In Aim 4, we will perform localization studies and functional analysis of the final four
members of the Drosophila Syt family to test their putative roles in DCV fusion and neuropeptide
release (Syt-α and Syt-β) or Ca2+-independent regulation of membrane trafficking (Syt12 and
Syt14). Using CRISPR technology to mutate and endogenously tag these Syt members, we are
in an exciting position to define the function of the entire Syt family within a single organism for
the first time. In summary, these experiments will provide a comprehensive picture of how the
Synaptotagmin family of proteins control synaptic membrane trafficking to regulate Ca2+-dependent neuronal communication from multiple intracellular compartments.

## Key facts

- **NIH application ID:** 10843897
- **Project number:** 5R01NS040296-23
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** J. TROY LITTLETON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $343,293
- **Award type:** 5
- **Project period:** 2000-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843897

## Citation

> US National Institutes of Health, RePORTER application 10843897, Characterization of the Drosophila Synaptotagmin Family (5R01NS040296-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10843897. Licensed CC0.

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