# Microglial remodeling of the extracellular matrix in memory circuits

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $72,484

## Abstract

PROJECT SUMMARY
Structural remodeling of synapses and circuits is essential to experience-dependent plasticity, as occurs during
the consolidation of learned experiences into long-term memory. Immune dysfunction has been implicated in
numerous cognitive disorders, including schizophrenia and neurodegenerative diseases, leading to increasing
interest in the function of brain-resident macrophages known as microglia, which are the dominant immune cell
in the brain parenchyma. We previously published that the IL-1 family cytokine Interleukin-33, which is made by
astrocytes during development, signals to its obligate receptor IL1RL1 expressed on microglia to promote
microglial activation and phagocytic function. In preliminary data that forms the basis for this proposal, we identify
a novel population of IL-33 expressing neurons in two adult brain regions: hippocampus and frontal cortex. In
detailed structural analyses in the hippocampus, we find that neuron-specific deletion of IL-33 or microglial-
specific deletion of IL-33 R leads to fewer dendritic spines, diminished markers of spine plasticity known as spine
head filopodia, and impaired neurogenesis. Furthermore, loss of this signaling pathway leads to deficits in
contextual fear conditioning: mice are able to normally learn to recognize a fear context but have a progressive
decrease in their ability to discriminate the fear context from a neutral context emerging at 15-30 days post
training. Mechanistically, we find that extracellular matrix proteins (the chondroitin sulfate proteoglycans brevican
and aggrecan) accumulate in the hippocampus of IL-33 deficient animals. We find that microglia engulf aggrecan,
and that loss of IL-33 signaling diminishes this engulfment. We also developed a neuronal gain of function
construct that constitutively secretes IL-33. We find this is sufficient to increase hippocampal spine numbers,
microglial ECM engulfment, and to clear ECM around dendritic spines. Based on these preliminary data, this
proposal will test the central hypothesis that neuron-derived IL-33 drives microglial remodeling of ECM to
promote circuit plasticity in support of memory consolidation. Aim One will explore the molecular regulation of
IL-33 release from neurons and its activity dependence, and test two candidate proteases mediating microglial
remodeling in response to IL-33. Aim Two will test the impact of this neuron-microglia signaling on the ECM
composition of the frontal cortex with a focus on perineuronal nets and determine its impact on connectivity of
the cortical microcircuit. Aim 3 will use calcium imaging in a contextual fear conditioning task to test how neuronal
activity patterns shift during the transition from recent to remote memories, addressing key questions regarding
the structural changes that underlie memory consolidation. Together, these studies will systematically dissect
the role of a novel cellular circuit regulating plasticity in the healthy brain. The outcome of ...

## Key facts

- **NIH application ID:** 10729587
- **Project number:** 3R01MH125000-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anna V Molofsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $72,484
- **Award type:** 3
- **Project period:** 2020-12-10 → 2023-06-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10729587

## Citation

> US National Institutes of Health, RePORTER application 10729587, Microglial remodeling of the extracellular matrix in memory circuits (3R01MH125000-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10729587. Licensed CC0.

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