# Axonal FMRP in Synaptic Development

> **NIH NIH R01** · FLORIDA STATE UNIVERSITY · 2022 · $21,414

## Abstract

Project Summary
This project will address the question of how abnormal synaptic development emerges in neurodevelopmental
disorders. Our overall hypothesis is that disorganized synaptic adhesion and delayed functional assembly of
synaptic vesicles (SVs) impair the formation and physiological maturation of presynaptic terminals, which triggers
subsequent developmental deficits in synaptic connectivity and function. We will test this hypothesis in Fragile X
syndrome (FXS), a leading inheritable form of autism and intellectual disability caused by functional loss of
Fragile X mental retardation protein (FMRP). Experimental observations will utilize the evolutionally conserved
endbulb terminals that are readily accessible for in vivo cell-autonomous characterizations in chicken embryos.
We will pursue two specific aims to test several important hypotheses derived from our preliminary studies.
 · In Specific Aim 1, we will determine the role of FMRP-regulated synaptic adhesion in presynaptic
 terminal formation. We hypothesize that axonal FMRP promotes terminal formation, stabilization, and
 selective retraction through developmentally profiled synaptic adhesion. To test this hypothesis, we will
 use cell-group specific and temporally-controlled genetic manipulations combined with in vivo live
 imaging to identify the exact actions of FMRP-mediated axon transport vs. protein translation in dynamic
 terminal turnover. We will also identify FMRP-regulated synaptic adhesion elements in developing
 terminals and assess the effects of correcting these elements on FMRP loss-induced presynaptic and
 axon alterations.
· In Specific Aim 2, we will determine the role of FMRP-regulated synaptotagmin (Syt) in functional
 maturation of presynaptic terminals. Syt1/2 are primary calcium sensors on SVs that trigger vesicle fusion
 and neurotransmitter release. We hypothesize that FMRP regulates presynaptic functional maturation by
 controlling the timely upregulation of Syt2 in nascent terminals. To test this hypothesis, we will determine
 the effects of expressing Syt2 on FMRP loss-induced deficits in SV activity, presynaptic protein
 machinery, and glutamate release. We will also determine the interplay between synaptic adhesion
 regulation and SV assembly under FMRP control using rescue studies.
Together, these results will identify an origin of defective synaptic phenotypes, a hallmark of neurodevelopmental
disorders. This knowledge is of vital importance because it will help establish a sensitive time window and identify
novel therapeutic candidates for preventing, or at least reducing, the progress of synaptic deficits in FXS and
other neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10675121
- **Project number:** 3R01MH126176-02S1
- **Recipient organization:** FLORIDA STATE UNIVERSITY
- **Principal Investigator:** Yuan Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $21,414
- **Award type:** 3
- **Project period:** 2021-08-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10675121

## Citation

> US National Institutes of Health, RePORTER application 10675121, Axonal FMRP in Synaptic Development (3R01MH126176-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10675121. Licensed CC0.

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