# The Microglial Developmental Index: A Novel Framework for Understanding the Role of Microglia in the Etiology of Autism Spectrum Disorder

> **NIH NIH F32** · DUKE UNIVERSITY · 2020 · $67,446

## Abstract

Project Summary
Autism spectrum disorder (ASD) currently affects 1 in 59 children in the United States. Prenatal exposure to
environmental factors like air pollution, which activate the immune system, have been associated with
increased ASD risk. However, the mechanisms by which adverse environmental exposures during pregnancy
lead to altered maturation of the fetal brain remain unknown. Microglia, the resident immune cells of the brain,
are key regulators of both the neural response to immune activation and the developmental organization of
neural circuits, making them uniquely poised to translate such adverse environmental exposures into neural
outcomes. Interestingly, recent studies suggest that prenatal challenges can alter the trajectory of brain
development (maturation), leading to aberrant neural circuit formation. We recently developed the microglial
developmental index (MDI) to objectively measure the global maturational state of microglia based on
transcriptomic sequencing. In mice, we showed that the MDI is accelerated by an acute immune challenge in
males only. Using human datasets, we found that the MDI is higher in ASD patients than in controls. Together,
these findings suggest that changes in microglial maturation represent a potential mechanism by which
immune insults increase ASD risk in sex-specific ways. Our lab has developed a novel mouse model of
prenatal immune activation which combines exposure to diesel exhaust particles (DEP) with a maternal
stressor (resource deprivation; MS). My preliminary data demonstrate that DEP/MS exposure impairs social
behavior in male offspring only. Therefore, in Aim 1, I will use next-generation RNA sequencing on isolated
microglia to test the hypothesis that DEP/MS exposure will accelerate the MDI in males only. My preliminary
data also show that DEP/MS exposure decreases dopamine D1 receptor (D1R) mRNA in the nucleus
accumbens (NAc). Moreover, we recently found that microglia-mediated synaptic pruning is critical to the
natural development of D1R in the NAc, and social behavior. Thus, in Aim 2, I will test the hypothesis that
DEP/MS exposure increases microglial pruning of NAc-D1Rs in males only. Finally, in Aim 3 I will test the
hypothesis that DEP/MS-induced changes in NAc-D1R are causal to DEP/MS-induced deficits in social
behavior. Specifically, I predict that a) local inhibition of microglial pruning in the NAc will prevent social
behavior deficits following DEP/MS and b), if these effects are dependent on D1R signaling specifically, then
this restoration will be attenuated by concurrent NAc-D1R antagonism. Together, this work will have an
important positive impact on both our basic understanding of the developmental biology of microglia, as well as
the specific contribution of neuro-immune signaling to the etiology of ASD.

## Key facts

- **NIH application ID:** 9990538
- **Project number:** 5F32ES029912-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Caroline Jackson Smith
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990538

## Citation

> US National Institutes of Health, RePORTER application 9990538, The Microglial Developmental Index: A Novel Framework for Understanding the Role of Microglia in the Etiology of Autism Spectrum Disorder (5F32ES029912-02). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/9990538. Licensed CC0.

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