# Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $73,701

## Abstract

Homeostatic signaling systems operate at synapses to enable flexible yet stable information
transfer in the nervous system. Defects in homeostatic signaling contribute to seizures,
excitotoxicity, cognitive decline, and neurodegeneration. Although much has been learned in
recent years about the expression mechanisms synapses employ to counteract perturbations to
neurotransmission, the pathways that rapidly initiate and chronically maintain homeostatic
signaling remains poorly understood. Here, we propose to determine the induction mechanisms
mediating homeostatic synaptic plasticity using the Drosophila neuromuscular junction as a
unique and powerful model system. At this glutamatergic synapse, pharmacologic or genetic
disruption to postsynaptic neurotransmitter receptors triggers a retrograde signaling system that
leads to a compensatory increase in presynaptic glutamate release to maintain stable synaptic
strength, referred to as presynaptic homeostatic potentiation (PHP). This process parallels similar
phenomena observed in a variety of other organisms, including mammalian central synapses. We
have recently discovered an E3 ubiquitin ligase adaptor that targets substrates in the postsynaptic
compartment and enables retrograde homeostatic signaling. We propose to first identify and
characterize postsynaptic targets of the homeostatic signaling system. Preliminary data suggests
a key component of the postsynaptic density is necessary for retrograde homeostatic signaling.
Next, we will define the induction mechanisms mediating the chronic expression of PHP and
determine the role of CaMKII in this process. Finally, we will interrogate the pharmacological
induction of PHP and test a hypothesis that trans-synaptic complexes mediate rapid retrograde
homeostatic signaling. These studies will leverage a synergistic combination of molecular genetic,
electrophysiological, and innovative functional imaging approaches at confocal, super resolution,
and ultrastructural levels to determine the induction mechanisms that initiate and maintain
retrograde homeostatic signaling. Together, these experiments will advance our understanding
of the fundamental mechanisms that endow synapses with the capacity to sense perturbations to
neurotransmission and adaptively modulate synaptic function to stabilize information transfer in
the nervous system.

## Key facts

- **NIH application ID:** 10757804
- **Project number:** 3R01NS091546-09S1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** DION KAI DICKMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $73,701
- **Award type:** 3
- **Project period:** 2015-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757804

## Citation

> US National Institutes of Health, RePORTER application 10757804, Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength (3R01NS091546-09S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10757804. Licensed CC0.

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