# Delineating the effects of sex on microglia in neurodevelopmental disorders

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2020 · $200,053

## Abstract

ABSTRACT
The incidence of many neurodevelopmental disorders including autism, schizophrenia, and cerebral palsy are
considerably higher in males than females. In the case of autism spectrum disorder (ASD), recent estimates
indicate that autism is 4 to 5 times more prevalent in males than females. The reason(s) for male vulnerability
and female protection in autism currently remain poorly understood. Improved understanding of the molecular
and cellular factors that underlie sex-bias in neurodevelopmental disorders will provide important new insights
into the etiologies of these complex disorders and will ultimately help to reveal much-needed biomarkers and
therapeutic targets for neurodevelopmental disease. In our preliminary studies, we have found that altering the
extent of maternal immune activation (MIA) influences development of autism-related behavioral abnormalities
in a sex-specific manner. More specifically, we demonstrate that low levels of gestational inflammation
promotes the development of autism-related phenotypes in male but not female offspring. In contrast,
enhancing MIA above a threshold promotes female-specific induction of neurodevelopmental disorders and
fetal reabsorption of male offspring. Interestingly, in our male-biased model of neurodevelopmental disease,
we observe that microglial pathways are hyperactivated in male offspring and not females. Moreover, we find
that anti-CSF1R knockdown of microglia and other myeloid cells during early gestation provides substantial
protection against the development of behavioral abnormalities in the MIA model. Microglia are tissue-resident
macrophages of the central nervous system (CNS) that aid in the clearance of debris and pathogens, and also
have been reported to participate in synaptic pruning, axon guidance, and neurogenesis. Recent studies have
begun to reveal sex-based differences in microglia activity that can contribute to distinct disease outcomes in
the adult brain. In contrast, little is currently known in regard to how sex modulates microglia responses in
neurodevelopmental disorders. Given our preliminary findings, we hypothesize that MIA results in sex-specific
alterations in microglia activities that can affect neurodevelopment. For this exploratory project, we propose
two aims to define how sex shapes microglia dynamics and function (Aim 1), and gene expression (Aim 2) in a
neurodevelopmental disorder model driven by MIA. Completion of the proposed studies will break new ground
in our understanding of how gestational exposure to inflammation can alter microglia responses in a sex-
specific manner and will provide new insights into the underpinnings of neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 9951114
- **Project number:** 5R21MH120412-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** John R Lukens
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $200,053
- **Award type:** 5
- **Project period:** 2019-06-11 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951114

## Citation

> US National Institutes of Health, RePORTER application 9951114, Delineating the effects of sex on microglia in neurodevelopmental disorders (5R21MH120412-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9951114. Licensed CC0.

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