# Mechanisms of activity-dependent microglia-neuron interactions in development and disease

> **NIH NIH RF1** · BOSTON CHILDREN'S HOSPITAL · 2022 · $91,907

## Abstract

Summary
Microglia-mediated synaptic pruning is highly regulated during developmental critical periods of synaptic
refinement, but its activation in vulnerable brain regions in disease models suggests that disease and
development share common regulators and mechanisms of pruning. Synaptic refinement is an activity-
dependent process where weak synapses are preferentially pruned. We hypothesize that neural activity is a key
upstream activator and regulator of microglia-mediated pruning in development and disease. In support of this
hypothesis, we and others demonstrated that microglia phagocytose synaptic elements and are capable of
sensing and responding to activity-related signals as they preferentially engulf less active synapses. However,
how microglia determine which synapses to engulf and which to avoid, and the identity of the upstream neuronal
signals that detect neural activity and transmit this information to microglia are not known.
 In the immune system, phagocytosis is carefully governed by both phagocytic, “eat me” and anti-
phagocytic, “don’t eat me” molecules. In the brain, we identified neuronal CD47, a “don’t eat me” signal protects
synapses from inappropriate removal. We further found that exposed phosphatidylserine (PS), an “eat me signal”
drives microglial recognition of synapses for engulfment. Furthermore, we have identified the tyrosine kinases,
Pyk2 and JAK2 as neuronal signals that are activated at inactive synapses and necessary for the elimination of
these inputs. Finally, we found that PS exposure is elevated early in the hippocampus in an Alzheimer's disease
(AD) mouse model. Based on these and other data, we propose to test the hypothesis that activity-dependent
signals within neurons, such as Pyk2 and JAK2, dynamically regulate "eat me" and "don't eat me" signals on
synapses to drive proper microglial phagocytosis of inactive synapses. We further hypothesize that aberrant
activation of such signals lead to abnormal synapse loss in neurodegenerative diseases, such as Alzheimer’s
Disease (AD). Specifically we aim to test the following: Aim 1) Investigate mechanisms of activity-regulated PS
exposure and function at developing synapses; Aim 2: Determine activity-dependent neuronal signaling that
regulates "eat me" and "don't eat me" signals for microglial engulfment; and Aim 3: Investigate the mechanisms
of early synaptic dysfunction and microglial synaptic targeting associated with AD. We will use interdisciplinary
in vivo and in vitro approaches with molecular/cell biological, histological, mouse genetic, imaging, and
electrophysiological techniques with various newly developed systems to address our aims. Our studies could
also provide new targets for therapeutic intervention, as restoring the balance of protective and elimination
signals could protect against synapse loss in early stages of AD and other diseases.

## Key facts

- **NIH application ID:** 10612683
- **Project number:** 3RF1NS092578-06S1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Beth Ann Stevens
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $91,907
- **Award type:** 3
- **Project period:** 2015-03-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10612683

## Citation

> US National Institutes of Health, RePORTER application 10612683, Mechanisms of activity-dependent microglia-neuron interactions in development and disease (3RF1NS092578-06S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10612683. Licensed CC0.

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