Roughly one in ten Americans lives with a neurodevelopmental condition, yet for decades scientists have struggled to answer a deceptively simple question: where, when, and how do these disorders begin? A new study from the Salk Institute for Biological Studies, published in Molecular Psychiatry, offers one of the most detailed answers to date, tracing the damage wrought by severe maternal illness during pregnancy all the way down to the chemical tags that govern gene activity in the fetal brain. By mapping epigenetic changes across development in the offspring of immune-activated mothers, the researchers have revealed a mechanism that may explain why infections during pregnancy raise the risk of autism spectrum disorder and related conditions—and they have done so at a resolution that links molecular marks to specific cell types, specific transcription factors, and specific genes already implicated in human autism.
The scientific backstory begins, fittingly, with the flu. Decades ago, epidemiologists noticed that mothers who contracted influenza during the second or third trimesters of pregnancy reported a higher incidence of psychiatric and neurodevelopmental disorders in their children. At the time, the observation was little more than a statistical curiosity. But when researchers later gained access to archived maternal blood samples, a clearer picture emerged: the risk appeared to track not with the virus itself but with the mother’s immune response to it. Chief among the suspects was interleukin-6, or IL-6, a signaling protein that stokes inflammation as part of the body’s defense against pathogens. Elevated IL-6 in the maternal bloodstream, it turned out, was the common thread. That discovery allowed scientists to build reliable rodent models of the phenomenon, in which a pregnant animal’s immune system is activated without any actual infection, reproducing the elevated risk of neurodevelopmental disorders in offspring.
What those models had largely lacked, however, was an epigenetic account of the damage. Most prior characterization of maternal immune activation in rodents was behavioral or electrophysiological—describing how the animals moved, responded to stimuli, or fired neuronal signals—without explaining what had changed inside the cells to produce those deficits. That gap is precisely what the Salk team, led by co-corresponding authors Margarita Behrens and Joseph Ecker, set out to close. Epigenetics refers to the layer of chemical tags and structural modifications that sits atop the base genetic sequence and determines which genes are turned on or off in a given cell. Unlike the genome itself, which is fixed at conception, the epigenome is malleable, making it a plausible target for environmental insults such as the inflammatory storm of maternal illness. If prenatal infection reshapes the developing brain, the epigenome is where that reshaping should leave its fingerprints.
To capture those fingerprints, the researchers used the field’s standard model of maternal immune activation: an injection of viral mimetic Poly(I:C), a synthetic double-stranded RNA that tricks the immune system into believing it has encountered an influenza virus. The treatment produces the same IL-6-driven inflammatory response as a genuine viral infection without introducing a pathogen. Using this model—referred to in the study as PIC-MIA—the team tracked epigenetic and transcriptional changes in the frontal cortex of mouse offspring from mid-gestation through two weeks after birth, comparing animals from immune-activated pregnancies with those from healthy pregnancies. The frontal cortex was the logical hunting ground: it is the brain region most associated with higher cognitive functions, and its development spans the entire window of vulnerability examined in the study.
The scale of the differences was striking. Across the developing cortex, the researchers documented thousands of epigenetic and gene-expression differences between the two groups. But the changes were not distributed evenly across all cell types. They concentrated, with remarkable specificity, in deep-layer neurons—a population of cortical cells that project long-range connections to other brain regions and are known to be generated during precisely the developmental window when maternal immune activation strikes. These cells form the structural backbone of cortical circuitry, and disruptions to their maturation ripple outward into the wiring of the entire brain.
At the molecular level, the team found that methylation patterns—the placement of small chemical methyl groups on the DNA—were especially altered in genomic regions that govern deep-layer neuron identity. The most consequential changes clustered at the binding sites of Tbr1, a transcription factor that serves as a master regulator of the developing brain, directing immature cells along the path to becoming deep-layer cortical neurons. Here the researchers encountered a genuine surprise. In the offspring of immune-activated mothers, Tbr1 was actually more abundant, and its binding sites were more heavily methylated than normal. Yet the genomic regions that Tbr1 typically regulates were downregulated, not upregulated. The explanation, the data suggest, is that the excess methylation was physically blocking Tbr1 from doing its job. The cell had produced more of its master architect, but methyl groups were sealing off the blueprints that architect needed to read. Deep-layer neuron development, deprived of proper Tbr1 direction, proceeded abnormally.
The implications deepened when the team cross-referenced their findings with the SFARI Gene Database, the reference catalog of autism-associated genomic alterations maintained for the autism research community. Among the high-confidence entries in that database—the genes scientists are most certain are genuinely linked to autism spectrum disorder—roughly twenty-five percent were dysregulated in the Salk dataset. In other words, the epigenetic disruptions caused by maternal immune activation were not scattered randomly across the genome; they landed preferentially on genes already known to matter for autism. That convergence between an environmental risk factor and a genetic risk landscape is exactly the kind of mechanistic bridge the field has been searching for, suggesting a route by which prenatal illness and inherited vulnerability may converge on the same developmental programs.
To confirm that the molecular changes had functional consequences, the researchers performed electrophysiological recordings on deep-layer neurons after the animals were born. The recordings confirmed what the epigenomic data predicted: the maturation of these neurons was measurably impaired in offspring of PIC-MIA pregnancies. The electrical properties that define healthy, fully developed cortical neurons were disrupted, demonstrating that the altered methylation and gene expression translated into altered neuronal function—a defect in the brain’s hardware, not merely its chemical profile.
The findings also carry an important caveat about determinism, one the researchers are careful to emphasize. Maternal infection changes the odds of neurodevelopmental outcomes; it does not seal them. “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 Joseph Ecker, professor and Salk International Council Chair in Genetics at Salk and a Howard Hughes Medical Institute investigator. This framing matters both scientifically and for public communication. The study identifies a risk-modifying mechanism, not an inevitability, and understanding the mechanism opens the door to interventions that could shift those odds back in the child’s favor—whether through maternal therapeutics that dampen harmful inflammation or through fetal interventions that protect vulnerable developmental programs.
Much remains unknown. The researchers still do not know exactly when during brain development the epigenetic damage occurs, or which stretch of pregnancy represents the window of greatest vulnerability to severe illness. “We are closer now to understanding the consequences of maternal infection, but this is only just the beginning of the story,” Ecker says. Behrens, for her part, frames the work as the payoff of a decade of methodical groundwork. “It’s just the tip of the iceberg. 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. Now we can approach questions with more detail. It’s going to be a lot of fun moving forward.” As single-cell epigenomic technologies continue to mature, the ability to ask where and when specific molecular events derail specific neuronal lineages will only sharpen, bringing the field closer to preventive strategies for a class of disorders that currently affects millions of families.
What makes the study resonate beyond the laboratory is its unifying logic. A mother’s feverish immune response, a chemical tag on DNA, a transcription factor locked out of its binding sites, a neuron that fails to mature, a brain whose circuitry carries the imprint into adulthood—these are not separate stories but a single causal chain, now traced end to end in a mammalian model. The work demonstrates the lasting impact of prenatal immune challenges on offspring health and adds a mechanistic foundation to a decades-old epidemiological observation. In doing so, it transforms a correlation once glimpsed in flu-season statistics into a testable, targetable biological pathway—one that may ultimately guide the development of maternal or fetal therapeutics designed to protect the developing brain from the collateral damage of the immune system’s own defense.
Subject of Research: The epigenetic and functional effects of maternal immune activation on developing cortical neurons in the mouse frontal cortex and their link to neurodevelopmental disorders such as autism spectrum disorder.
Subject of Research: Biology
Article Title: Maternal immune activation disrupts epigenomic and functional maturation of cortical excitatory neurons
Article References: Lai, C.-Y., Arzavala, J., Pinto-Duarte, A., Wang, S., Li, J., Liu, H., Osteen, J., Gomez Castanon, R., Nery, J., Powell, S. B., Ecker, J. R., Mukamel, E. A., & Behrens, M. M. (2026). Maternal immune activation disrupts epigenomic and functional maturation of cortical excitatory neurons. Molecular Psychiatry. https://doi.org/10.1038/s41380-026-03856-1
Image Credits: AI Generated
DOI: 10.1038/s41380-026-03856-1
Keywords: maternal immune activation, epigenetics, autism spectrum disorder, Tbr1, DNA methylation, deep-layer neurons, frontal cortex, IL-6, Poly(I:C), neurodevelopmental disorders, Salk Institute, Molecular Psychiatry
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Harold Sullivan. (September 8, 2026). How Maternal Severe Illness During Pregnancy Can Impair Fetal Brain Development. Scienmag. https://scienmag.com/how-maternal-severe-illness-during-pregnancy-can-impair-fetal-brain-development/
Harold Sullivan. “How Maternal Severe Illness During Pregnancy Can Impair Fetal Brain Development.” Scienmag, 8 September 2026, https://scienmag.com/how-maternal-severe-illness-during-pregnancy-can-impair-fetal-brain-development/. Accessed 8 September 2026.
Harold Sullivan. “How Maternal Severe Illness During Pregnancy Can Impair Fetal Brain Development.” Scienmag. September 8, 2026. https://scienmag.com/how-maternal-severe-illness-during-pregnancy-can-impair-fetal-brain-development/
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