# Dissecting ADAM10 function in microglia-mediated synapse elimination

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $32,882

## Abstract

7. Project Summary/Abstract
 The goal of this proposal is to dissect the molecular signaling between microglia and neurons
that regulates synapse elimination in response to changes in sensory experience. Despite compelling
evidence that microglia, the resident brain macrophages, play important roles in eliminating synapses in
development and disease, the precise neuron-to-microglia molecular signaling that drives this process is poorly
understood. I recently discovered a signaling pathway necessary for microglia-mediated synapse elimination by
utilizing the well-described circuitry of the mouse barrel cortex circuit as a model to manipulate sensory
experience and dampen neuronal activity. Here I found microglia robustly engulf synapses in the barrel cortex
following either whisker lesioning or trimming, and that this engulfment is dependent on the microglial CX3CR1
receptor and its canonical neuronal ligand, CX3CL1, but not complement. Using single-cell RNAseq I also found
that neuronal Cx3cl1 was not differentially regulated in the cortex following whisker removal, but the protease
Adam10, known to cleave membrane-bound CX3CL1 into a soluble form, is increased following lesioning.
Importantly, pharmacological inhibition of ADAM10 resulted in synapse elimination defects that phenocopied
CX3CR1 and CX3CL1-deficient mice. These data suggest that post-translational modification of neuronal
CX3CL1 by ADAM10 is required to regulate microglial synapse elimination in the cortex following whisker
removal. Several exciting new questions have now arisen, which I will tackle in this proposal: 1) What is the
cellular source of ADAM10 and is it localized to synapses (Aim 1)? 2) Do other subcortical synapses within the
barrel circuit remodel via ADAM10-CX3CL1-CX3CR1 signaling and does this differ between whisker lesioning
and trimming (Aim 2)? I hypothesize ADAM10 is derived from layer IV excitatory neurons to regulate microglia-
mediated synapse remodeling and that ADAM10 signaling is specific for cortical synapse rewiring after whisker
trimming and lesioning, but not for sub-cortical synapse remodeling. To test this hypothesis, I have acquired
powerful in vivo molecular genetic tools to manipulate ADAM10 function in specific cells. I have also developed
collaborations to learn and perform cutting-edge whole tissue clearing by iDISCO to assess structural remodeling
of entire circuits. Finally, I have a strong mentoring team that includes my mentor Dr. Dorothy Schafer with
expertise in microglial function within neural circuits, my co-mentor Dr. Andrew Tapper with expertise in structural
and functional mapping of brain circuits, and collaborators with expertise in iDISCO. Together, I am in a strong
position to molecularly dissect how ADAM10 modulates neuron-microglia signaling necessary for remodeling
brain circuits. This could be highly relevant for neurodegenerative disease where microglial dysfunction, synapse
loss, and ADAM10 have been implicated. In the p...

## Key facts

- **NIH application ID:** 9992103
- **Project number:** 1F31NS117053-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Georgia Gunner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,882
- **Award type:** 1
- **Project period:** 2020-03-30 → 2023-03-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992103

## Citation

> US National Institutes of Health, RePORTER application 9992103, Dissecting ADAM10 function in microglia-mediated synapse elimination (1F31NS117053-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9992103. Licensed CC0.

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