Study Links Maternal Infections to Fetal Brain Development

By Dr. Chinta SidharthanReviewed by Laura ThomsonSep 18 2026

Researchers have long suspected that infections during pregnancy can influence brain and neuronal development in the fetus and play a role in neurodevelopmental disorders such as autism spectrum disorder (ASD). A recent study published in Molecular Psychiatry examined how a mother's immune response to infections during gestation reshapes the developing brains of her offspring at the molecular level.

Maternal immune activation, often triggered by viral or bacterial infection during pregnancy, is increasingly being recognized as an environmental contributor to neurodevelopmental conditions such as schizophrenia and ASD.

Researchers have explored this process in rodents using polyriboinosinic-polyribocytidylic acid, or Poly(I:C), a synthetic molecule that mimics viral infection and provokes an inflammatory response in pregnant animals. Offspring exposed to Poly(I:C) during gestation display behavioral traits reminiscent of human neurodevelopmental disorders, including difficulties with social interaction and cognitive flexibility.

Yet despite decades of research, scientists have struggled to pinpoint exactly when maternal immune activation inflicts molecular damage during brain development. Earlier work in adult rodent brains identified abnormal deoxyribonucleic acid (DNA) methylation patterns, but these adult studies could not identify the critical developmental window during which fetal brain development was most vulnerable or which specific brain cell types were affected.

Multi-Stage Study

The researchers designed a multi-stage mouse study spanning gestation through early adulthood to trace how maternal immune activation affects brain development over time. For this, they used a mouse model in which excitatory neurons could be genetically labeled and isolated by marking the neurons with a fluorescent tag on their nuclear membrane.

Pregnant mice received a single injection of Poly(I:C) or a saline control on embryonic day 12.5, corresponding to mid-gestation. Because immune responses to the injection varied across litters, the researchers used maternal weight loss after injection as a screening criterion and excluded litters that did not show a sufficiently strong response.

The researchers collected brain tissue from offspring at several developmental time points, including embryonic day 15, birth, postnatal day 13, and postnatal day 70. They then isolated excitatory neurons from the frontal cortex based on fluorescence, performed ribonucleic acid (RNA) sequencing to measure gene expression changes, and identified the samples showing the clearest treatment effects for further analysis based on gene expression patterns.

The team also applied whole-genome bisulfite sequencing to a subset of these samples to map DNA methylation across the genome at single-base resolution. They used statistical tools to identify regions of the genome altered by treatment. The researchers then searched these regions for transcription factor binding motifs and compared the affected genes to the Simons Foundation Autism Research Initiative (SFARI) database of autism-linked genes.

The team measured the electrical firing properties of pyramidal neurons in cortical layers 2/3 and 5/6 during the first two postnatal weeks to connect molecular changes to actual neuronal function.   

What Were the Key Findings?

Maternal immune activation caused the greatest disruption to gene expression and DNA methylation in excitatory neurons at birth, with effects diminishing substantially by the second postnatal week. At birth, the researchers identified 2,113 genes with abnormally high expression and 2,295 genes with abnormally low expression in the frontal cortex of exposed offspring. In comparison, they observed only 132 affected genes before birth and 55 affected genes two weeks after birth.

Many of the disrupted genes at birth encoded proteins essential for synapse formation, including calcium and potassium channels, glutamate receptors, and scaffolding proteins that anchor synaptic connections. Furthermore, roughly a quarter of high-confidence autism-linked genes cataloged in the SFARI database showed abnormal expression in these newborn mice.

DNA methylation analysis also revealed a parallel pattern, where regions of the genome that normally lose methylation during early development remained abnormally methylated in exposed offspring, while regions that should gain methylation stayed under-methylated, pointing to a general delay in neuronal maturation.

Binding sites for Tbr1, a transcription factor critical for the identity of deep-layer cortical neurons, were particularly affected, becoming hypermethylated even though Tbr1 itself was more highly expressed. This mismatch suggested that maternal immune activation separated Tbr1 production from its normal regulatory function, leaving the genes it typically controls unable to respond even as the transcription factor itself became more abundant.

Electrophysiological recordings supported these molecular findings and showed that deep-layer neurons in exposed animals failed to develop the more stable resting electrical properties typically seen with age.

The authors noted that their methylation dataset may be biased toward animals with stronger treatment responses, since samples were selected partly based on gene expression severity. The study also examined only male offspring, which raises the question of whether female offspring respond differently to maternal immune activation.

Conclusion

Maternal immune activation produces its most damaging effects on cortical neurons around the time of birth rather than earlier in gestation, and disrupts the coordinated maturation of gene expression, DNA methylation, and electrical activity in deep-layer neurons.

These results offer a clearer timeline for when environmental risk factors during pregnancy intersect with fetal brain development and can inform future strategies to identify and potentially mitigate neurodevelopmental risk.