Estrogen Receptor β as a Candidate Regulator of Sex Differences in the Maternal Immune Activation Model of ASD.

Madeline L Arnold,Kaoru Saijo

doi:10.3389/fnmol.2021.717411

Madeline L Arnold, Kaoru Saijo

Open Access

https://doi.org/10.3389/fnmol.2021.717411

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Abstract

Interestingly, more males are diagnosed with autism spectrum disorder (ASD) than females, yet the mechanism behind this difference is unclear. Genes on the sex chromosomes and differential regulation by sex steroid hormones and their receptors are both candidate mechanisms to explain this sex-dependent phenotype. Nuclear receptors (NRs) are a large family of transcription factors, including sex hormone receptors, that mediate ligand-dependent transcription and may play key roles in sex-specific regulation of immunity and brain development. Infection during pregnancy is known to increase the probability of developing ASD in humans, and a mouse model of maternal immune activation (MIA), which is induced by injecting innate immune stimulants into pregnant wild-type mice, is commonly used to study ASD. Since this model successfully recaptures the behavioral phenotypes and male bias observed in ASD, we will discuss the potential role of sex steroid hormones and their receptors, especially focusing on estrogen receptor (ER)β, in MIA and how this signaling may modulate transcription and subsequent inflammation in myeloid-lineage cells to contribute to the etiology of this neurodevelopmental disorder.

Highlights

Many neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), attentiondeficit/hyperactivity disorder (ADHD), and schizophrenia, show sex differences (Waddell and McCarthy, 2012; Hanamsagar and Bilbo, 2016; Hill, 2016; McCarthy, 2016; Bordeleau et al, 2019; May et al, 2019; Lord et al, 2020; Merikangas and Almasy, 2020); yet the mechanisms behind these observations are poorly understood
We focus on ERβ because (1) ERβ is broadly expressed in mouse brain (Mitra et al, 2003; Fan et al, 2006) and (2) we previously showed that ERβ could regulate inflammation in microglial cells (Saijo et al, 2011)
We have discussed the hypothesis that ERβ-mediated repression of inflammation in brain myeloid-lineage cells may contribute to the male bias observed in an maternal immune activation (MIA)-induced ASD mouse model

Summary

INTRODUCTION

Many neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), attentiondeficit/hyperactivity disorder (ADHD), and schizophrenia, show sex differences (Waddell and McCarthy, 2012; Hanamsagar and Bilbo, 2016; Hill, 2016; McCarthy, 2016; Bordeleau et al, 2019; May et al, 2019; Lord et al, 2020; Merikangas and Almasy, 2020); yet the mechanisms behind these observations are poorly understood. Our single-cell RNA-sequencing (scRNA-seq) analysis showed that the activation of fetal BAMs in response to MIA was dependent upon fetal Trif, an essential signaling molecule downstream of TLR3 (Nichols et al, 2020, preprint) These findings indicate that MIA leads to fetal innate immune signaling in BAMs. in validating our scRNA-seq data, we found that MIA causes BAMs in the choroid plexus, but not meningeal BAMs or microglia, to have increased expression of S100a8 and 9, key inflammatory genes that are known to induce chemotaxis and enhance inflammation

C Hypothesis I

CONCLUSION AND FUTURE DIRECTIONS