How severe illness during pregnancy sometimes alters neurodevelopment

Neurodevelopmental disorders, such as autism spectrum disorder and ADHD, affect approximately 10% of the American population, but it's challenging to determine when and how these conditions develop. However, research has found a pattern: severe illness during pregnancy increases the risk of neurodevelopmental disorders in offspring.

To understand this connection, researchers at the Salk Institute studied the epigenomes of mouse frontal cortex cells during fetal development, with some mice having healthy mothers and others with immune-activated mothers. Their study, published in Molecular Psychiatry, revealed thousands of epigenetic differences between the two groups, with the offspring of immune-activated mothers exhibiting distinct epigenomes in deep-layer neurons compared to healthy counterparts.

Many of these epigenetic differences were found near genes linked to autism spectrum disorder. The findings suggest that prenatal immune challenges have lasting effects on brain circuitry, carrying into adulthood. The study began with the discovery that mothers who had influenza infections during the second or third trimester of pregnancy reported a higher incidence of psychiatric disorders in their offspring decades later.

This phenomenon was later linked to the mother's immune response to the infection, particularly elevated levels of IL-6, a protein that promotes inflammation as part of the immune response. Scientists created rodent models to replicate this phenomenon, using the viral mimetic Poly(I:C) to induce immune activation in pregnant mice.

The study found that PIC-MIA changed epigenetic programming in the frontal cortex during development and into adulthood, leading to distinct alterations in gene activity and methylation patterns. Specifically, methylation patterns were particularly different in areas of the genome that help make deep-layer neurons, especially near Tbr1 binding sites, which are major regulators for the developing brain.

Despite an influx of Tbr1, increased methylation blocked Tbr1 from doing its job, defining deep-layer neurons. These findings are related to autism spectrum disorder, as 25% of high-confidence autism-associated genes were also dysregulated in the study dataset. The study confirms that infection changes the odds of neurodevelopmental disorder, but not everyone who gets sick during pregnancy will have a child with a neurodevelopmental disorder.

The research adds novel insight into the underlying causes of these disorders and demonstrates the lasting impact of prenatal immune challenges on offspring health outcomes.