# Retrograde Signaling for Homeostatic Control of Synaptic Transmission

> **NIH NIH R21** · GEORGETOWN UNIVERSITY · 2021 · $422,840

## Abstract

Abstract
The nervous system is remarkably complex and malleable in terms of developmental and learning-related
plasticity. Homeostatic signaling systems, operating at the level of individual neurons and neural circuits, act to
maintain the function of individual nerve cells and neural circuitry, thereby ensuring robust and stable brain
function. Defective homeostatic signaling is directly linked to the cause and progression of neurological diseases
including epilepsy, schizophrenia, Autism Spectrum Disorders (ASD), and neurodegeneration. The molecular
design and implementation of homeostatic signaling in the nervous system is only just beginning to emerge. We
use the Drosophila neuromuscular junction (NMJ) as a model synapse to delineate the molecular mechanisms
governing homeostatic control of synaptic transmission. At the Drosophila NMJ (a glutamatergic synapse),
inhibition of postsynaptic glutamate receptors leads to a compensatory increase in presynaptic neurotransmitter
release to maintain stable synaptic strength. This phenomenon is called Presynaptic Homeostatic Plasticity, and
is evolutionarily conserved in organisms ranging from fly, to mouse, and to human. Presynaptic homeostatic
plasticity is initiated by a reduction of glutamate receptor function at the postsynaptic side, but is expressed as
an enhancement of presynaptic neurotransmitter release. Therefore, retrograde signaling is required to offset
the postsynaptic perturbation, and to restore muscle excitation to its initial baseline level. We previously
demonstrated that α2δ-3, an auxiliary subunit of presynaptic calcium channels, is required for presynaptic
homeostatic plasticity. Loss of α2δ-3 blocks both the rapid induction and sustained expression of homeostatic
plasticity, due to a failure to potentiate presynaptic calcium influx. α2δ proteins reside at the extracellular face of
presynaptic release sites, an ideal location for mediating rapid, homeostatic signaling. But how the presynaptic
α2δ-3 protein functions as part of this retrograde signaling system, to receive and relay information across the
synapse, remains to be elucidated. By using the α2δ-3 protein as bait, we have identified putative α2δ-3 binding
partners localized in the postsynaptic compartment with mass-spectrometry method. We hypothesize that the
biochemical interaction between presynaptic α2δ-3, and its postsynaptic binding partners, are critical for the
transsynaptic homeostatic plasticity mechanisms necessary to stabilize synaptic physiology. We propose to first
perform formal genetic and biochemical analyses, to study the function of the putative retrograde signaling
molecules have been identified. Second, we will perform functional studies to explore the molecular and cellular
mechanisms underlying retrograde signaling in presynaptic homeostatic plasticity, through electrophysiological,
biochemical, calcium imaging, and super-resolution imaging methods. Together, the results of these studies will
advanc...

## Key facts

- **NIH application ID:** 10186987
- **Project number:** 1R21NS121284-01
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Tingting Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $422,840
- **Award type:** 1
- **Project period:** 2021-03-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186987

## Citation

> US National Institutes of Health, RePORTER application 10186987, Retrograde Signaling for Homeostatic Control of Synaptic Transmission (1R21NS121284-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10186987. Licensed CC0.

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