Developmental modulation of schizophrenia risk gene methylation in offspring exhibiting cognitive deficits following maternal immune activation.

Maternal infection during pregnancy has been shown in epidemiological studies to increase the risk of neurodevelopmental disorders, like schizophrenia, in the developing fetus. 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 these epigenetic mechanisms are altered and contribute to abnormal neurodevelopment remains limited. This lack of understanding has slowed progress in identifying therapeutic targets in particular for cognitive symptoms of neurodevelopmental disorders. Focusing on the cortex of offspring exposed to MIA who showed cognitive impairments, at both prenatal and postnatal stages, here we measured tissue concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), using the SAM/SAH ratio as an indicator of overall methylation capacity. We also analyzed changes in the expression and activity of DNA methyltransferases (DNMTs), as well as DNA methylation (DNAm) patterns. Our findings revealed that MIA increased the SAM/SAH ratio and elevated both DNMT expression and activity in the fetal cortex. 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 signalling. These novel insights help establish a critical connection between MIA and epigenetic changes that contribute to cognitive deficits similar to those observed in schizophrenia.