# Microglia-dependent mechanisms governing neural circuit plasticity

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $418,750

## Abstract

The goal of this proposal is to determine how microglia and sensory experience integrate to
remodel synapses into precise, functional brain maps. Trillions of synapses form highly precise
topographic maps in the brain representing each part of the body. These maps are shaped and maintained by
sensory experience (vision, touch, etc.), including elimination of less active synapses and formation and
maintenance of other synapses. Despite over 50 years of research, the underlying mechanisms by which
experience dictates removal or maintenance of specific synapses still remains an open question. We made the
initial exciting and unexpected observation that microglia, the resident CNS macrophages, engulfed and
eliminated a subset of less active synapses in the developing retinogeniculate system. Further, reducing
microglia-mediated engulfment of synapses by 50% (complement receptor 3 KO) resulted in sustained
increases in retinogeniculate synapse number. This work established a new way of thinking about synaptic
remodeling and inspired several important new questions: Is microglia-mediated synaptic remodeling
necessary for achieving functional circuits? Do microglia remodel synapses in the adult brain? How does
neural activity regulate microglia-mediated synaptic remodeling? The retinogeniculate system was limiting
for addressing these questions. We required a robust system for studying synaptic remodeling that involved
plasticity of synapses throughout life, tractable assays for measuring function, and a topographic arrangment
with high spatial and temporal resolution. The mouse barrel cortex fit all these critera and will enable us to test
the hypothesis that experience regulates microglia to shape developing and mature syanpses into functional
brain circuits. Our new preliminary data show for the first time that microglia engulf excitatory thalamocortical
(TC) synapses in the developing barrel cortex and following sensory deprivation (whisker removal) in the
neonate. Further, mice deficient in microglia (colony stimulating factor 1 receptor KO; CSF1R KO) have defects
in the development of approriate barrel architecture and TC input elimination following whisker deprivation is
completely blocked in mice deficient in a microglia-specific chemokine receptor (fractalkine receptor KO,
CX3CR1 KO). We will now use a combination of high resolution static and functional imaging and molecular
biology in the mouse barrel cortex to: 1) Determine whether microglia sculpt developing cortical circuits into
functional brain maps (Aim 1). 2) Determine whether microglia regulate experience-dependent plasticity of
cortical maps in the neonate and adult (Aim 2). 3) Identify how microglia remodel synapses in response to
changes in neural activity (Aim 3). Answers will uncover new mechanisms regulating how sensory experience
regulates the development of structural and functional brain maps, will identify new ways to achieve plasticity
in the adult brain, and will provide n...

## Key facts

- **NIH application ID:** 10140418
- **Project number:** 5R01MH113743-05
- **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:** 2021
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140418

## Citation

> US National Institutes of Health, RePORTER application 10140418, Microglia-dependent mechanisms governing neural circuit plasticity (5R01MH113743-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140418. Licensed CC0.

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