A La Jolla research team has identified how severe illness during pregnancy can alter fetal brain development, changing the activity of genes tied to autism spectrum disorder.
The Salk Institute study, published Wednesday, Sept. 2, in the journal Molecular Psychiatry, found thousands of epigenetic differences in the brain cells of mouse offspring born to immune-activated mothers compared with those born to healthy mothers. Epigenetic changes are chemical modifications layered on top of DNA that determine which genes get switched on or off.
About 25% of the high-confidence autism-associated genes cataloged in the SFARI Gene Database were also dysregulated in the Salk team's data, according to the institute's announcement. The SFARI database tracks 418 high-confidence and strong-candidate autism risk genes out of 1,231 total genes linked to the disorder.
"Among high-confidence genes … around 25% of the database was also dysregulated in our dataset," said Jessica Arzavala, a graduate student researcher in the lab of co-corresponding author Margarita Behrens and co-first author of the study.
The research traces a line from decades-old observations that mothers who contracted influenza during the second or third trimester reported higher rates of psychiatric disorders in their children. Later blood-sample analysis linked the effect to elevated levels of IL-6, a protein that promotes inflammation, in the maternal bloodstream, according to the Salk announcement.
Behrens, a research professor at Salk, said most prior work on the connection had been behavioral or electrophysiological. Her team wanted to examine the epigenetic layer, she said, to understand what changes during development might drive those observations.
Using a compound called Poly(I:C) that mimics influenza exposure, the researchers triggered immune activation in pregnant mice and then tracked the offspring's frontal cortex neurons from mid-gestation through two weeks after birth. They found that methylation patterns were especially altered in genome regions that build deep-layer neurons. A key protein called Tbr1, which regulates early brain development, was blocked from binding to its normal targets by the excess methylation, the study found.
Electrical recordings of those deep-layer neurons after birth confirmed the developmental impairment. The changes persisted into adulthood.
Co-corresponding author Joseph Ecker, a professor and Howard Hughes Medical Institute investigator at Salk, cautioned in the announcement that infection shifts the odds rather than guaranteeing a disorder. Not every illness during pregnancy will lead to a neurodevelopmental condition in the child, he said.
Neurodevelopmental conditions affect about 10% of the U.S. population, according to the Salk announcement. The CDC reported in 2025 that autism spectrum disorder affects 1 in 31 children in the United States, up from 1 in 36 in 2023.
The study's authors said further research should guide efforts to develop maternal or fetal therapies that could prevent or reduce the risk of such disorders. Scientists still do not know exactly when during pregnancy the epigenetic changes occur or which trimester poses the greatest vulnerability, the announcement noted. Co-first author Chi-Yu Lai and co-corresponding author Eran Mukamel of UC San Diego also contributed to the work.
