Maternal Illness Reshapes Fetal Brain Through Epigenetic Changes, Study Shows

About one in ten Americans lives with a neurodevelopmental condition—autism spectrum disorder, ADHD, or one of several others. For decades, scientists have struggled to understand where these conditions originate, when they take root, and what sets them in motion. But one pattern has emerged clearly: when a pregnant woman becomes severely ill, her offspring face a measurably higher risk of developing these disorders later in life.

Researchers at the Salk Institute set out to understand the mechanism behind this observation. They studied the epigenomes—the chemical tags and modifications that sit atop the genetic code itself—of mouse brain cells during fetal development. Some mice came from healthy mothers; others came from mothers whose immune systems had been artificially activated to mimic infection. The work, published in Molecular Psychiatry on September 2, 2026, revealed thousands of epigenetic differences between the two groups. The offspring of immune-activated mothers showed particularly distinct patterns in deep-layer neurons, the cells that form the brain's foundational architecture. Many of these differences clustered near genes already known to be associated with autism spectrum disorder.

The story of this discovery begins much earlier. Decades ago, epidemiologists noticed that children born to mothers who had contracted influenza during the second or third trimester showed higher rates of psychiatric illness in adulthood. When researchers examined blood samples from these mothers, they found the culprit: elevated levels of IL-6, a protein that triggers inflammation as part of the immune response. This finding allowed scientists to build animal models of the phenomenon, creating pregnant mice whose immune systems responded as if they had encountered a virus. "That was a long time ago," says Margarita Behrens, a research professor at Salk and one of the study's leaders. "When epidemiologists analyzed this phenomenon more recently using blood samples from mothers, they uncovered that it was likely linked to the mother's immune response to the infection."

The Salk team used a viral mimic called Poly(I:C) to trigger immune activation in pregnant mice, then tracked what happened to the epigenomes of their offspring's brain cells from mid-gestation through two weeks after birth. They looked for changes in gene activity and for methylation—a specific type of epigenetic modification in which small chemical tags attach to the genetic code. The results were striking. Mice born to immune-activated mothers showed distinct alterations in both gene activity and methylation patterns. The methylation changes were especially pronounced in regions of the genome responsible for building deep-layer neurons. Even more specifically, the sites where a protein called Tbr1 normally binds—a crucial regulator of developing brain architecture—were more heavily methylated than normal. This mattered because Tbr1 acts as a master switch for deep-layer neuron development. Despite the presence of more Tbr1 protein, the increased methylation was blocking it from doing its job. The genes Tbr1 typically activates were instead being silenced.

When the researchers compared their findings to the SFARI Gene Database, an authoritative catalog of genes linked to autism spectrum disorder, they found that about 25 percent of the high-confidence autism-associated genes in that database were dysregulated in their affected mice. After birth, electrophysiological recordings confirmed that the deep-layer neurons in these offspring were indeed impaired—the epigenetic changes had translated into functional brain abnormalities that persisted into adulthood.

The implications are significant but not deterministic. As Joseph Ecker, a professor of genetics at Salk and a Howard Hughes Medical Institute investigator, notes: "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." The study demonstrates that prenatal immune challenges leave lasting marks on the developing brain, but many questions remain unanswered. Scientists still do not know exactly when during pregnancy these epigenetic changes occur, or which windows of fetal development are most vulnerable to maternal illness.

The work opens a path toward new treatments. Understanding the epigenetic mechanisms at play could guide the development of maternal or fetal therapies designed to prevent or reduce the risk of neurodevelopmental disorders. But as Behrens emphasizes, this is early terrain. "We are distilling all these things that we have been doing for ten years—analyzing epigenomes for years and years to get to the point that we can ask these questions," she says. "Now we can approach questions with more detail. It's going to be a lot of fun moving forward."