# Synapse Engulfment by Oligodendrocyte Precursor Cells: A New Mechanism of Circuit Refinement in the Developing Brain

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2024 · $625,414

## Abstract

PROJECT SUMMARY
 The establishment of synaptic connectivity during brain development involves the initial formation of an
overabundance of synapses followed by a refinement process in which some of these synapses are maintained
while others are eliminated. The precise elimination of excess synapses is driven by sensory experience during
critical periods of early postnatal life. Impairments in sensory-dependent synapse elimination contribute to
neurodevelopmental disorders such as autism, underscoring the importance of this process for the proper
development and function of neural circuits. However, although neurodevelopmental disorders are growing in
prevalence at an alarming rate, therapeutic strategies for treating them are scarce in part due to a lack of insight
into the factors that control synapse elimination in the healthy brain. A key goal of this proposal is to uncover
novel cellular and molecular mechanisms underlying the elimination of synapses downstream of experience,
thereby laying the groundwork for new therapeutic approaches to treat disorders of postnatal brain development.
 Work in the visual system of the mouse has revealed that non-neuronal brain cells, predominantly
microglia and astrocytes, coordinate synapse elimination before the onset of visual experience by phagocytosing
excess synapses. However, data suggest that these cells may not be major regulators of synapse elimination
during late phases of development that are coordinated by visual experience. On the contrary, we recently
discovered a key role for a less well understood class of glia, oligodendrocyte precursor cells (OPCs), in
eliminating synapses in response to experience through synaptic phagocytosis. This result is consistent with
wide-spread speculation that OPCs, while predominantly appreciated for their differentiation into mature
oligodendrocytes, play key roles in the brain beyond myelination. In line with this possibility, our data suggest
that OPCs are essential for shaping functional neural circuits during the maturation of the brain.
 In this application, we propose a multi-disciplinary strategy to test the hypothesis that the engulfment of
synapses by OPCs is a core mechanism underlying the sensory-dependent elimination of functional synapses
in the developing brain. In Aim 1, we will employ viral and transgenic tools to characterize the spatio-temporal
dynamics and activity-dependent basis of synaptic engulfment by OPCs using in vivo two-photon microscopy. In
Aim 2, we will apply physiological and behavioral assays to determine the consequences of synaptic engulfment
by OPCs on brain function in the intact animal. In Aim 3, we will merge unbiased transcriptomic and CRISPR-
based screening techniques with a candidate-based approach focused on the phagocytic receptor Lrp1 to reveal
molecular pathways underlying the engulfment of synapses by OPCs. Altogether, we expect these studies to
establish synapse engulfment by OPCs as a new mechanism linking expe...

## Key facts

- **NIH application ID:** 10806222
- **Project number:** 5R01NS131486-02
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Lucas M Cheadle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,414
- **Award type:** 5
- **Project period:** 2023-03-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806222

## Citation

> US National Institutes of Health, RePORTER application 10806222, Synapse Engulfment by Oligodendrocyte Precursor Cells: A New Mechanism of Circuit Refinement in the Developing Brain (5R01NS131486-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10806222. Licensed CC0.

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