# Estrogen receptor (ER)β-mediated repression of prenatal inflammation in fetal microglia and its impact on autism

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $325,775

## Abstract

Abstract
 One in 68 children are diagnosed with autism spectrum disorders (ASD) in the US, yet there are
currently no fundamental therapies available. Furthermore, epidemiological research suggests that nearly five
times more boys than girls are affected by ASD, but the mechanisms behind this sex dimorphism are not well
understood. It is known that both genetic and environmental factors are involved in ASD pathogenesis. Of the
environmental factors, epidemiology suggests that prenatal inflammation induced by maternal infection is
associated with an increased risk of ASD, yet the mechanisms behind this link still need to be elucidated.
 Our lab has been working on understanding how environmental factors affect normal brain
development and functions by focusing on how microglia, resident immune cells in the central nervous system,
control innate immune responses in the brain. More specifically, we are interested in whether sex hormones
and their corresponding nuclear receptors (Estrogen Receptors and Androgen Receptor) may be able to
induce changes in gene expression and epigenetic regulation in microglia that can restore normal CNS
functions and improve neuroinflammatory diseases such as ASD. Our central hypothesis for this proposal is
that innate immune signaling, such as toll-like receptor (TLR)-mediated inflammation in fetal microglia, is
involved in inducing specific, ASD-like behavior changes. Furthermore, we predict that the expression levels of
anti-inflammatory ERβ ligands in fetal microglia determine their sensitivity to prenatal inflammation and
contribute to the male bias observed in ASD. We will test these hypotheses using mouse models of prenatal
inflammation-induced ASD.
 The primary goal of this proposal is to understand how differential responses to TLR-mediated prenatal
inflammation can affect long-term fetal microglial transcription and epigenetic regulation, resulting in ASD-like
behaviors. Moreover, we will determine whether modulation of ERβ-mediated transcription and epigenetic
regulation can restore normal microglial functions affected by prenatal inflammation, thus ameliorating ASD-
like behaviors in offspring. The expected overall impact of this proposal is that it will expand the mechanistic
understanding of distinct maternal and fetal TLR-mediated signaling pathways by clarifying how they are
associated to specific behavior changes observed in ASD. We will also fully elucidate how ERs and their
ligands contribute to the male bias observed in ASD and how these ligands can restore homeostasis in
microglia to improve ASD-like behaviors in a mouse model.

## Key facts

- **NIH application ID:** 9920736
- **Project number:** 5R01HD092093-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Kaoru Saijo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,775
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920736

## Citation

> US National Institutes of Health, RePORTER application 9920736, Estrogen receptor (ER)β-mediated repression of prenatal inflammation in fetal microglia and its impact on autism (5R01HD092093-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920736. Licensed CC0.

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