Estrogen Receptor β Protects Against ASD-like Behavior in Mice

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting 1 in 68 children in America and approximately 1% of the population worldwide. Although the underlying neurobiological mechanism for ASD pathophysiology is not clear, recent studies have suggested the role of endoplasmic reticulum stress in ASD. Moreover, our recent study has shown that ER stress induces ASD-like behavior including communication deficits, social deficits, depressive behavior, and repetitive behavior mechanism in mice. ASD is generally thought to be gender-specific with 5 times more males diagnosed with the disorder than females suggesting a potential role of female sex hormones in ASD. We recently showed that estrogen receptor β (ERβ) is reduced in the prefrontal cortex of ASD subjects as compared to age- and gender-matched control subjects. However, the mechanisms behind this deficit are not known. 

Objectives: This study aims to determine whether estrogen receptor β signaling can protect against endoplasmic reticulum (ER) stress induced behavioral deficits in mice.

Methods: ER stress was induced by administering tunicamycin (1mg/kg I.P.) to mice. Protein levels were measured by western blot analysis whereas RT-PCR was used for gene expression analysis. Behavioral tests were performed including ultrasonic vocalization recordings, social interaction test, grooming test, marble bury test, forced swim test, tail suspension test, and open field test. The role of ERβ was examined by pharmacological as well as genetic manipulations in mice. 

Results: We found that ER stress in mice reduces ERβ signaling in mouse frontal cortex. ER stress induced ASD-like behavior such as social deficits, depressive-like behavior, increases in obsessive behaviors, and communication deficits. Moreover, boosting ERβ signaling could reverse ER stress-induced deficits in ASD-like behavior in mice.

Conclusions: ERβ is a possible target for treatment of ASD and related neurodevelopmental disorders.