# Investigating novel mechanisms that underlie glial-mediated synapse elimination in development and aging

> **NIH NIH K99** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $112,439

## Abstract

Project Summary
Formation and maintenance of synaptic connections between appropriate neuronal partners is essential for
proper nervous system function. Indeed, impairments in either initial synapse formation or in subsequent
developmental synapse elimination underlie many neurodevelopmental disorders. Synapse elimination that
occurs outside of appropriate developmental contexts underlies synaptic loss associated with age-related
cognitive decline and in neurodegenerative diseases. Thus, defining the mechanisms that underlie the regulation
of synapse number will provide insight into how appropriate connections are formed during development, and
these pathologies of synapse elimination.
Despite its essential role in nervous system development and function throughout life, we still know little about
the mechanisms underlying this process. We do know, however, that glia are required. In order to identify novel
glial regulators of synapse development, I completed a forward genetic screen in Drosophila, and identified 91
molecules that, when knocked down in glia, alter synapse number. Among these molecules is the immune
receptor Crq, which I found is required for glial elimination of synapses in development. This proposal will focus
on understanding Crq’s role in synapse elimination, in order to gain insight into the larger questions of which
synapses undergo developmental synapse elimination, the mechanisms underlying the specificity of this
process, and whether these same mechanisms are re-used in pathological synapse loss associated with aging.
Aim 1 will address the question of which synapses undergo developmental elimination across the nervous
system and evaluate which of these are Crq-dependent. I have recently developed an inducible pre-synaptic
label that makes this work possible, and will generate inducible postsynaptic labels as part of this aim. Aim 2 will
use proximity labeling to identify the neuronal ligand(s) for Crq that act to specify which synapses undergo
elimination, and will identify how expression and localization of these ligands are regulated. Aim 3 will define
which synapses are lost with aging, and identify whether Crq acts as a common mediator of synaptic loss in
development and aging. I will also perform a targeted screen based on a recent transcriptional profiling
experiment I completed to identify additional glial regulators of age-related synaptic loss.
Together, these studies will address the mechanisms by which synapses are targeted for elimination and how.
This is a key question in achieving the larger goal of understanding how neurons and glia work together to
create and maintain appropriate synaptic connections throughout life. Dissecting these mechanisms will also
provide insight into the process of age-related synaptic loss that underlies age-related cognitive decline. In
addition, performing this work will allow me to address existing gaps in my technical skills that will allow me to
carry out my long-term resear...

## Key facts

- **NIH application ID:** 10883653
- **Project number:** 5K99NS133298-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Taylor Reagan Jay
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $112,439
- **Award type:** 5
- **Project period:** 2023-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883653

## Citation

> US National Institutes of Health, RePORTER application 10883653, Investigating novel mechanisms that underlie glial-mediated synapse elimination in development and aging (5K99NS133298-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883653. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*