# Physiologic roles of Type I interferon responsive microglia in brain development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $681,230

## Abstract

PROJECT SUMMARY
The immune system plays key roles in brain development, but immune challenges in early life can also increase
the risk for neurodevelopmental disorders including autism and schizophrenia. Microglia, the dominant immune
cells of the brain parenchyma, mediate this brain-immune axis by regulating neural circuit development in
response to immune cues. A relatively unexplored function of microglia in early brain development is the
engulfment of whole neurons, which may engage distinct phagocytic mechanisms from those used, for example,
to remodel synapses. In preliminary experiments, we have identified a molecularly distinct subset of microglia in
the early postnatal mouse somatosensory cortex (P5) that is actively engulfing whole neurons. These microglia
express a Type I Interferon (IFN-I) responsive molecular signature and have a unique phagocytic morphology in
situ, frequently engulfing several neurons at a time. While these cells are rare in the typically developing cortex,
they expand 20-fold in somatosensory cortex in a partial whisker deprivation model that accelerates
developmental circuit remodeling. We find that both global and microglial-specific deletion of the IFN-I receptor
(Ifnar1) leads to dysmorphic microglial with enlarged phagolysosomes and an accumulation of neurons with
double strand DNA breaks, a damage/hyperexcitability marker. Our central hypothesis is that Type I Interferon-
responsive microglia promote somatosensory circuit maturation by eliminating specific neurons in early postnatal
development. We will test this hypothesis in three specific aims. In Aim 1, we will follow up on preliminary data
showing that Ifnar1-deficient juvenile animals have altered numbers of deep layer cortical neuronal subtypes,
with an increase in excitatory neuronal density, as well as hyperreactive sensory responses to whisker
stimulation. We will further examine these phenotypes in global and microglial-specific Ifnar1 deletion by
electrophysiology, behavior, and immunohistochemistry. Aim 2 will expand on our preliminary data showing that
exogenous IFN-I (IFN-) is sufficient to expand IRMs and reduce the number of neurons with dsDNA breaks.
Using our whisker deprivation and pharmacologic gain of function models, we will probe the sources and targets
of IFN-I in the developing brain, and the circuit impact of excess IFN-I signaling. Aim 3 follows up on our data
that identifies dsRNA sensing via MAVS as the potential molecular pattern that amplifies IFN-I responses in
these microglia. We will use in vivo conditional deletion and in vitro cocultures to define the sources and cellular
targets of dsRNA in developing cortex. Our long-term goal is fully define the unexpected implications of microglial
engulfment of neurons in cortical development, and more broadly, to define the novel homeostatic role of this
innate immune pathway in the developing nervous system. 

## Key facts

- **NIH application ID:** 10992496
- **Project number:** 1R01MH135137-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anna V Molofsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $681,230
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992496

## Citation

> US National Institutes of Health, RePORTER application 10992496, Physiologic roles of Type I interferon responsive microglia in brain development (1R01MH135137-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10992496. Licensed CC0.

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