# Molecular Genetics of Synaptic Plasticity

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $436,339

## Abstract

Developing neural circuits are actively remodeled as synapses are created in new locations and dismantled in
others. These dynamic changes are driven by the combined effects of genetic programs and neural activity
that together shape the architecture and function of mature circuits. Synaptic plasticity has been observed
throughout animal phylogeny which suggests that the underlying pathways are conserved and thus can be
investigated in simple model organisms that are amenable to experimental analysis. Here we propose to use
the nematode, C. elegans, to define a development program that remodels the synaptic architecture of a
GABAergic circuit. During early larval development, DD-class GABAergic neurons undergo a dramatic
remodeling program in which the presynaptic apparatus exchanges locations with postsynaptic components
within the DD neuronal process. To reveal the mechanism of this effect, we are investigating the functional
roles of ~20 conserved genes that we have determined are transcriptionally regulated to drive GABA neuron
remodeling. Our work has shown that two of these targets, the DEG/ENaC cation channel protein, UNC-8, and
ARX-5/p21, a conserved component of the Arp2/3 complex, function together in an activity-dependent
mechanism that dismantles the presynaptic domain. Aim 1 tests the hypothesis that UNC-8 cation transport
elevates intracellular calcium to drive presynaptic disassembly and that this effect is regulated by calcium-
dependent phosphorylation. This goal is important because members of the DEG/ENaC protein family have
been implicated in learning and memory but the mechanism that links DEG/ENaC function to synaptic plasticity
is poorly understood. Aim 2 tests the hypothesis that the UNC-8 function triggers an actin-dependent
endocytic mechanism that recycles presynaptic components for reassembly at new locations. These
experiments derive from our surprising discovery that a key functional protein of the Arp2/3 actin-branching
complex is transcriptionally regulated to effect synapse removal and that newly identified components of an
endocytic recycling pathway are involved. Together, these approaches offer a powerful opportunity to delineate
intricate molecular pathways that link neural activity to genetic programming in the execution of a synaptic
remodeling mechanism. Moreover, the conservation of C. elegans remodeling components in mammals
argues that this work is likely to reveal fundamental mechanisms that regulate synaptic plasticity in the human
brain.

## Key facts

- **NIH application ID:** 10101697
- **Project number:** 5R01NS106951-04
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Laura Bianchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $436,339
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101697

## Citation

> US National Institutes of Health, RePORTER application 10101697, Molecular Genetics of Synaptic Plasticity (5R01NS106951-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10101697. Licensed CC0.

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