# How Do Synaptic Connections Change in Demyelinating Disease?

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $408,108

## Abstract

Schafer, Dorothy P.
Project Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), which
has a profound, currently intractable, neurodegenerative component--a large, unmet clinical need. In many
neurodegenerative diseases, one of the earliest degenerative events is synapse dysfunction and loss. There is
also synapse loss in MS, but the underlying molecular mechanism(s) remains an open question. The overall
hypothesis of this proposal is that complement-dependent signaling underlies synapse loss in
demyelinating disease in a subset of vulnerable neurons. This is largely based on our initial findings in the
developing retinogeniculate circuit demonstrating that classical complement cascade proteins C1q and C3
localize to synapses and that phagocytic microglia engulf and eliminate synapses via the C3 receptor,
complement receptor 3 (CR3). Strikingly, we have new evidence that a subset of retinogeniculate synapses are
also engulfed by microglia, leading to synapse loss, in MS and in multiple MS-relevant animal models of
demyelinating disease (e.g. non-human primate and mouse experimental autoimmune encephalomyelitis (EAE)
models). We further identified that this synapse loss can occur early prior to demyelination, axon degeneration,
or cell death, but is coincident with peripheral immune cell infiltration, reactive microgliosis, and increased levels
of complement C1q and C3. However, unlike development, C3, but not C1q, is localized to synapses. Finally,
inhibiting C3 specifically at retinogeniculate synapses in mouse EAE prevents microglial synapse engulfment,
synapse loss, and visual dysfunction. These experiments establish C3 and microglia as key regulators of
synapse loss in MS-relevant demyelinating disease and open up several new questions that we will explore: 1)
What cells produce complement necessary for synapse elimination in demyelinating disease (Aim 1)? 2) Does
microglial complement receptor CR3 regulate synapse loss in demyelinating disease (Aim 2)? 3) Which RGCs
are most vulnerable to complement-mediated synapse elimination and later degeneration (Aim 3)? To address
these questions, we will continue to use the retinogeniculate circuit. This is a highly tractable and powerful
system for studying synaptic changes and it is highly relevant to MS, where inflammation of the optic nerve (i.e.
optic neuritis) occurs in upwards of 50% of patients and results in prolonged, often permanent, visual dysfunction.
We will now use a combination of cell-specific molecular genetics and high-resolution imaging of retinogeniculate
synapses in the mouse EAE model to molecularly dissect synapse loss in inflammatory demyelinating disease.
Results could uncover novel targets aimed at slowing or preventing neurodegeneration in MS, which could be
broadly applicable to other neurodegenerative disease with synapse loss and neuroinflammation (Alzheimer’s
disease, frontotemporal dementia, etc.).

## Key facts

- **NIH application ID:** 10774236
- **Project number:** 5R01NS117533-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Dorothy Patricia Schafer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $408,108
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10774236

## Citation

> US National Institutes of Health, RePORTER application 10774236, How Do Synaptic Connections Change in Demyelinating Disease? (5R01NS117533-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10774236. Licensed CC0.

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