byIngrid Fadelli, Phys.org

RRBS gene list overlaps with schizophrenia risk genes. Figure demonstrates the overlap between the differentially methylated genes identified by the RRBS analysis in this study to other gene datasets (refer to Supplementary Methods Section 1.4) including: schizophrenia variant genes (SZ_GENE), genes differentially methylated in schizophrenia (SZ_METH), genes differentially expressed in schizophrenia (SZ_EXP), and genes differentially methylated in the PFC of male mice exposed to MIA (MIA_WGBS). Credit: Woods et al. (Molecular Psychiatry, 2025).

The health of mothers during pregnancy has long been known to play a role in the lifelong mental and physical health of offspring. Recent studies have found that contracting an infection during pregnancy can increase the risk that offspring will develop some neurodevelopmental disorders, conditions that are associated with the atypical maturation of some parts of the brain.

An infection is an invasion of pathogens, such as bacteria, viruses, fungi or parasites, which can then multiply and colonize host tissues. Findings suggest that when an expecting mother contracts an infection, her immune system can respond to it in ways that could impact the development of the fetus.

Researchers at University of Manchester and Manchester Metropolitan University recently carried out a study aimed at further investigating the processes through which maternal infections during pregnancy could increase the risk that offspring will develop schizophrenia later in life. Schizophrenia is a typically debilitating mental health condition characterized by hallucinations, false beliefs about oneself or the world (e.g., delusions) and cognitive impairments.

The findings of the team's study, outlined in a paperpublishedinMolecular Psychiatry, shed light on epigenetic shifts prompted by infection that could potentially be linked to a higher genetic risk of offspring developing schizophrenia. Epigenetic processes are changes in the expression of genes prompted by biological processes, which do not alter the DNA sequence of a living organism.

"Maternal infection during pregnancy has been shown inepidemiological studiesto increase the risk of neurodevelopmental disorders, like schizophrenia, in the developing fetus," wrote Rebecca M. Woods, Harry G. Potter and their colleagues in their paper.

"Epigenetic mechanisms are thought to play a crucial role in linking maternal immune activation (MIA) to a higher risk of schizophrenia in offspring by disrupting normal brain development. However, our knowledge of how theseepigenetic mechanismsare altered and contribute to abnormal neurodevelopment remains limited."

Various past studies have tried to uncover the epigenetic mechanisms that could link a mother's infection during pregnancy to a higher risk that their offspring will experience schizophrenia. Identifying these mechanisms could ultimately help to develop new preventative or therapeutic interventions forneurodevelopmental disorders.

The main objective of the recent study by Woods, Potter and their colleagues was to shed new light on the epigenetic underpinnings of maternal infection, by analyzing data collected from rats. Their analyses specifically focused on processes that might affect the expression of genes that are linked to a higher risk of developing schizophrenia in humans.

"Focusing on the cortex of offspring exposed to MIA who showed cognitive impairments, at both prenatal and postnatal stages, we measured tissue concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), using the SAM/SAH ratio as an indicator of overall methylation capacity," explained the authors of the paper. "We also analyzed changes in the expression and activity of DNA methyltransferases (DNMTs), as well as DNA methylation (DNAm) patterns."

The results of the team's experiments and analyses revealed that the activation of a pregnant rat's immune system due to infection influenced the ratio between SAM and SAH molecules in the fetus. The ratio between these molecules is known to be an indication of the ability of cells to undergo methylation, a biological process that controls the expression of genes.

"Our findings revealed that MIA increased the SAM/SAH ratio and elevated both DNMT expression and activity in the fetal cortex," wrote the authors. "Surprisingly, these changes were not present after birth but resurfaced in adulthood, coinciding with cognitive deficits. These methylation pathway changes in adulthood were accompanied by altered DNAm patterns, with differentially methylated genes linked to schizophrenia risk and enriched in pathways related to neurodevelopment and neuronal signaling."

The researchers were able to pinpoint epigenetic changes following infection in pregnant female rats that resulted in pups exhibiting cognitive deficits resembling those associated with schizophrenia. Their findings could soon pave the way for further investigations on this topic and could potentially contribute to the future development of more effective drugs to treat the cognitive symptoms ofschizophrenia, such as attention, memory and language deficits.

© 2025 Science X Network

More information: Rebecca M. Woods et al, Developmental modulation of schizophrenia risk gene methylation in offspring exhibiting cognitive deficits following maternal immune activation, Molecular Psychiatry (2025). DOI: 10.1038/s41380-025-03147-1 . Journal information: Molecular Psychiatry