Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice

William A Carlezon,Beate C Finger,Yan Li,Samantha M Landino,James O Robbins,Christopher J Mcdougle,Abigail J Alexander,Kwang-Soo Kim,Emery L Mokler,Galen Missig,Vadim Y Bolshakov,Woori Kim

doi:10.1038/s41598-019-53294-z

Abstract

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD), a neurodevelopmental syndrome with higher prevalence in males than females. Here we examined the effects of early-life immune system activation (EIA)—comprising regimens of prenatal, early postnatal, or combined (“two-hit”) immune activation—on the core behavioral features of ASD (decreased social interaction, increased repetitive behavior, and aberrant communication) in C57BL/6J mice. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C) on gestational day 12.5 to produce maternal immune activation (MIA). Some offspring also received lipopolysaccharide (LPS) on postnatal day 9 to produce postnatal immune activation (PIA). EIA produced disruptions in social behavior and increases in repetitive behaviors that were larger in males than in females. Ultrasonic vocalizations (USVs) were altered in both sexes. Molecular studies revealed that EIA also produced prominent sex-specific changes in inflammation-related gene expression in the brain. Whereas both sexes showed increases in pro-inflammatory factors, as reflected by levels of mRNA and protein, expression of anti-inflammatory factors was decreased in males but increased in females. Our findings demonstrate that EIA can produce sex-specific behavioral effects and immune responses in the brain, and identify molecular processes that may contribute to resilience in females.

Highlights

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD), a neurodevelopmental syndrome with higher prevalence in males than females
In a prototypical maternal immune activation (MIA) regimen[13], pregnant dams are treated on embryonic day 12.5 (E12.5) with polyinosinic:polycytidylic acid (Poly I:C)—a toll-like receptor-3 (TLR3) agonist that simulates an innate response to viral infection—which exposes offspring to immune
With respect to behavioral endpoints, MIA (Poly I:C administered on E12.5) tended to have minimal effects, whereas postnatal immune activation (PIA) (LPS administered on postnatal day 9 (PND9)) produced more pronounced effects

Summary

Introduction

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD), a neurodevelopmental syndrome with higher prevalence in males than females. We examined the effects of early-life immune system activation (EIA)—comprising regimens of prenatal, early postnatal, or combined (“two-hit”) immune activation—on the core behavioral features of ASD (decreased social interaction, increased repetitive behavior, and aberrant communication) in C57BL/6J mice. Postnatal immune activation (PIA) involving early developmental treatment of the offspring with lipopolysaccharide (LPS)—a TLR4 agonist that simulates an innate response to bacterial infection—can cause a variety of behavioral changes in mice that resemble features of ASD16. To further explore the possibility of accumulating effects, we developed a “two-hit” EIA regimen in mice that involves MIA (using Poly I:C) followed by PIA (using LPS) This paradigm enables studies of whether MIA can increase the susceptibility of offspring to the effects of a second immune challenge early in postnatal development. Considering previous reports of sex-dependent effects of both prenatal and postnatal immune activation[22,23], we examined both sexes across behavioral and molecular endpoints

Methods

Results

Conclusion