How severe illness during pregnancy sometimes alters neurodevelopment

Neurodevelopmental conditions, which include autism spectrum disorder, ADHD (attention-deficit/hyperactivity disorder) and more, affect around 10% of the American population. Despite their prevalence, it has remained difficult to pin down where, when and how many of these disorders begin.

Yet scientists have noticed one pattern: Severe illness during pregnancy can increase the risk of neurodevelopmental disorders in offspring.

To figure out why this may be the case, Salk Institute researchers monitored the epigenomes of mouse frontal cortex cells throughout fetal development, some with healthy mothers and others with immune-activated mothers.

Their study, published in Molecular Psychiatry, shows thousands of epigenetic differences between the two groups.

The offspring of immune-activated mothers showed particularly distinct epigenomes in deep-layer neurons compared with their healthy counterparts. Many of the epigenetic differences were found near genes linked to autism spectrum disorder. The findings also demonstrated the genetic influence prenatal immune challenges have on neurodevelopment—creating lasting changes in brain circuitry that carry into adulthood.

What is known about the impact of maternal illness on neurodevelopment?

It all started with the flu. Decades ago, scientists noticed that mothers who had experienced influenza infections during the second or third trimester of their pregnancies reported a higher incidence of psychiatric disorders in their offspring.

“That was a long time ago,” says co-corresponding author Margarita Behrens, Ph.D., a research professor at Salk. “When epidemiologists analyzed this phenomenon more recently using blood samples from mothers, they found that it was likely linked to the mother’s immune response to the infection.”

More specifically, the researchers found elevated IL-6 levels in the maternal bloodstream. IL-6 is an important protein that helps promote inflammation as part of the immune response. With this new information, scientists were able to create rodent models of the phenomenon in which influenza infection leads to immune activation and an elevated risk of neurodevelopmental disorders.

“Today, the model is very well characterized,” continues Behrens. “But most of that characterization is behavioral or electrophysiological—not epigenetic. We wanted to look at what epigenetic changes were happening throughout development to potentially cause the behavioral, psychiatric and electrophysiological observations other scientists have made.”

Epigenetic changes are chemical tags and modifications made on top of the base genetic code. These alterations determine which genes do or don’t get expressed and, in turn, the function of the entire cell. Importantly, the epigenome is more malleable than the genetic code it rests on—meaning it could be changing during fetal neurodevelopment in response to maternal immune activation.

What epigenetic changes occur after a healthy or immune-challenged pregnancy?

The “very well characterized” model that the Salk team used relies on the viral mimetic Poly(I:C), a treatment that mimics influenza exposure. Using this model, the team asked: How does Poly(I:C) maternal immune activation (PIC-MIA) change epigenetic programming in the frontal cortex during development and into adulthood?

The researchers analyzed mouse neurons in the frontal cortex after PIC-MIA from mid-gestation through two weeks after birth. They searched for changes in gene activity following maternal immune activation, as well as for a kind of epigenetic change called methylation, in which small chemical tags (methyl groups) are attached to the underlying genetic code.

Mice from PIC-MIA pregnancies had distinct alterations to their gene activity (transcriptome) and methylation patterns. It turned out that methylation patterns were especially different in areas of the genome that help make deep-layer neurons.

Even more specifically, sites where the transcription factor Tbr1 binds—a protein that acts as a major regulator for the developing brain—were more methylated than normal in deep-layer neuron-specific regions at birth. While there was more Tbr1, the scientists were surprised to find that areas of the genome Tbr1 typically interacts with were downregulated.

Despite an influx of Tbr1 available to bind to the genome, increased methylation was blocking Tbr1 from doing its job defining deep-layer neurons. What’s more, these Tbr1 sites are also strongly related to autism spectrum disorder.

“We compared our findings to the SFARI Gene Database, an established database of autism spectrum-associated genomic alterations that’s very well known within the autism research community,” says Jessica Arzavala, co-first author of the study and graduate student researcher in Behrens’s lab.

“Among high-confidence genes—those we are most sure are correctly mapped and linked to autism spectrum disorder—around 25% of the database was also dysregulated in our dataset.”

After the offspring were born, the team also collected electrophysiological recordings of the deep-layer neurons to understand whether they were altered by the observed transcriptional and epigenetic changes caused by PIC-MIA pregnancies. Their analysis confirmed that deep-layer neuron development in offspring was impaired by MIA in the pregnant mouse model.

“Infection changes the odds of whether neurodevelopment is affected—not everyone who gets sick during pregnancy is going to definitively have a child with a neurodevelopmental disorder,” says co-corresponding author Joseph Ecker, Ph.D., a professor and Salk International Council Chair in Genetics at Salk and a Howard Hughes Medical Institute investigator.

How does understanding epigenetics help progress neurodevelopmental disorder treatment?

The study adds novel insight into the underlying causes of some neurodevelopmental disorders. It demonstrates the lasting impact of prenatal immune challenges on offspring health outcomes. Further unraveling these details should guide future efforts to develop maternal or fetal therapeutics that prevent or reduce the risk of such disorders.

Before that, many questions remain. Scientists still don’t know exactly when these epigenetic changes occur during brain development or the most vulnerable time for severe illness to strike during pregnancy.

“We are closer now to understanding the consequences of maternal infection, but this is only just the beginning of the story,” says Ecker.

“It’s just the tip of the iceberg,” adds Behrens. “We are distilling all these things that we have been doing for 10 years—analyzing epigenomes for years and years to get to the point that we can ask these questions. Now we can approach questions with more detail. It’s going to be a lot of fun moving forward.”

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

Full profile →

Advertisements

Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

Full profile →