Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates

Abstract

A subset of women who are exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental or neuropsychiatric disorder. Although epidemiology studies have primarily focused on the association between maternal infection and an increased risk of offspring schizophrenia (SZ), mounting evidence indicates that maternal infection may also increase the risk of autism spectrum disorder (ASD). A number of factors, including genetic susceptibility, the intensity and timing of the infection, and exposure to additional aversive postnatal events, may influence the extent to which maternal infection alters fetal brain development and which disease phenotype (ASD; SZ; other neurodevelopmental disorders) is expressed. Preclinical animal models provide a test bed to systematically evaluate the effects of maternal infection on fetal brain development, determine the relevance to human CNS disorders, and to evaluate novel preventative and therapeutic strategies. Maternal immune activation (MIA) models in mice, rats, and nonhuman primates suggest that the maternal immune response is the critical link between exposure to infection during pregnancy and subsequent changes in brain and behavioral development of offspring. However, differences in the type, severity, and timing of prenatal immune challenge paired with inconsistencies in behavioral phenotyping approaches have hindered the translation of preclinical results to human studies. Here we highlight the promises and limitations of the MIA model as a preclinical tool to study prenatal risk factors for ASD, and suggest specific changes to improve reproducibility and maximize translational potential.

Poly(I:C) alters placental and fetal brain amino acid transport in a rat model of maternal immune activation

“…17,18 When administered at mid-gestation (gestational day [GD] 14-15 in rats or 12.5-13.5 in mice), the viral mimetic poly(I:C) induces MIA which can modulate the emergence of specific behaviors or neurological phenotypes associated with neurodevelopmental disorders in the adult offspring. 17,18 When administered at mid-gestation (gestational day [GD] 14-15 in rats or 12.5-13.5 in mice), the viral mimetic poly(I:C) induces MIA which can modulate the emergence of specific behaviors or neurological phenotypes associated with neurodevelopmental disorders in the adult offspring.…”

Interleukin-1β/Interleukin10 Ratio Produced by Monocytes as a Biomarker of Neuroinflammation in Autism

“…In animal models of ASD, mothers who were induced to have inflammation during mid-gestation, had offspring that developed ASD symptoms after birth. This animal model of ASD is known as the maternal immune activation (MIA) model, and has been widely used [3,4]. Additional evidence of immune mediated inflammation comes from the analysis of transcriptome and protein expression in the post-mortem brains of ASD subjects [5].…”

Prenatal Inflammation Dampens Neurogenesis and Enhances Serotonin Transporter Expression in the Hippocampus of Adult Female Rats

“…Experimentally, rodents born to immune-challenged dams during pregnancy showed signs of behavioral alterations assimilated to several brain ailments such as schizophrenia, anxiety, and depression [1, 20, 21]. In the present study, we explored the long-lasting impact of prenatal immune challenge on brain plasticity and behavior in female offspring.…”