# Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $619,005

## Abstract

Project Summary
The goal of this proposal is to determine how microglia and astrocytes communicate to remodel
synapses. Trillions of synapses form highly precise circuit maps in the brain. These maps are shaped and
maintained by sensory experience (vision, touch, etc.), including elimination of less active synapses and f
maintenance and strengthening of other synapses. Despite over 50 years of research, the underlying
mechanisms by which activity dictates removal of some synapses, but not others, remains an open question.
We made the initial discovery that microglia, a resident central nervous system (CNS) macrophage, engulf and
eliminate less active synapses in the developing retinogeniculate and barrel cortex circuits. In the last funding
cycle, we showed that removal of whiskers on one side of the snout in neonates resulted in microglial engulfment
and elimination of thalamocortical (TC) synapses in the corresponding barrel cortex. Unlike the retinogeniculate
circuit, this was not regulated by complement. Instead, microglia failed to engulf and eliminate TC synapses in
mice deficient in neuronal fractalkine (CX3CL1)-to microglial fractalkine receptor (CX3CR1) signaling. This work
established that diverse glial mechanisms regulate activity-dependent synapse remodeling and opened up new
questions: Do microglia remodel synapses in the adult brain? With evidence that astrocytes also engulf synapses
in other CNS circuits, are astrocytes also involved in barrel cortex synapse remodeling? If so, do they
communicate with microglia to regulate this process? Our new preliminary data show that astrocytes do not
engulf synapses in response to whisker removal in neonates, but rather they reduce their contact with synapses
in a CX3CL1-dependent manner. Also, microglia no longer engulf TC synapses following whisker removal in
older animals, concomitant with elevated astrocyte synapse ensheathment. Cell-specific RNAseq following
whisker removal further reveals canonical Wnt signaling as a putative mechanism by which microglia signal to
astrocytes to regulate synapse ensheathment. We now propose a novel model by which microglia regulate
astrocyte ensheathment of synapses in an activity and CX3CL1-CX3CR1-Wnt dependent manner. In turn,
microglia gain access to engulf and remove TC synapses. We will now leverage the power of the barrel cortex
circuit with cell-specific genetic approaches to: 1) Define the developmental window for CX3CL1-CX3CR1-
dependent microglial synapse engulfment and astrocyte synapse ensheathment (Aim 1). 2) Determine if
astrocyte ensheathment of synapses impacts microglia-dependent synapse remodeling (Aim 2). 3) Identify how
microglia regulate astrocyte ensheathment of synapses (Aim 3). Answers will address how some synapses are
eliminated by glia while others are left intact—a key open question in the field with implications for a variety of
neurodevelopmental disorders and neurodegenerative diseases with underlying changes in synaptic
con...

## Key facts

- **NIH application ID:** 10452923
- **Project number:** 2R01MH113743-06
- **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:** 2022
- **Award amount:** $619,005
- **Award type:** 2
- **Project period:** 2017-07-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452923

## Citation

> US National Institutes of Health, RePORTER application 10452923, Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling (2R01MH113743-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10452923. Licensed CC0.

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