# Role of SNARE Interactions in Central Synapse Function

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $441,790

## Abstract

Project-Summary
Recent studies have identified a large number of variants in SNARE (soluble N-ethylmaleimide-sensitive factor
attachment protein receptor) machinery components such as SNAP25 that give rise to intractable early
childhood brain disorders. In this project, we will use rodent hippocampal neurons as well as human embryonic
stem cell derived neurons and a unique SNAP25 variant knock-in mouse model, to fully define the synaptic
transmission and plasticity deficits associated with key disease causing SNAP25 variants and evaluate their
responsiveness to neurotherapeutics. Importantly, our studies have identified SNAP25 variants that
dramatically alter spontaneous release with limited or no effect on properties of action potential evoked
neurotransmission. As spontaneous release process is a key determinant of synapses' homeostatic state and
responsiveness to certain neurotherapeutics, we expect that the effects of these mutations will go beyond their
immediate impact on the release process and alter synaptic plasticity as well as treatment response. Overall,
we aim to test the hypothesis that disease causing neurotransmitter release machinery variants elicit crucial
downstream signaling defects altering plasticity mechanisms that affect responsiveness to therapeutics via
three Specific Aims. The first aim will address synaptic mechanisms adversely affected by SNAP25 variants
using electrophysiology, single synapse optical imaging, electron-microscopy and super-resolution imaging.
The second aim will focus on examining SNAP25 variant induced synaptic deficits in human neurons. In this
system, we will evaluate the impact of experimental therapeutics that elicit homeostatic synaptic plasticity on
SNAP25 variant induced deficits. Finally, aim 3 will examine circuit specific synaptic transmission and plasticity
deficits in a unique SNAP25 variant mouse model. Information attained from these studies will provide new
insight to the synaptic substrates that are affected not only by these disorders but also a number of
neuropsychiatric and neurological disorders with synaptic abnormalities including major depressive disorder,
autism, schizophrenia and neurodegeneration.

## Key facts

- **NIH application ID:** 10876800
- **Project number:** 2R01NS134128-22A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Ege T Kavalali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,790
- **Award type:** 2
- **Project period:** 2003-12-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876800

## Citation

> US National Institutes of Health, RePORTER application 10876800, Role of SNARE Interactions in Central Synapse Function (2R01NS134128-22A1). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10876800. Licensed CC0.

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