Maternal immune activation induces methylation changes in schizophrenia genes

Abstract

Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Infection driven maternal immune activation (MIA) during pregnancy is a key environmental risk factor. However, little is known about how MIA during pregnancy could contribute to adult-onset schizophrenia. In this study, we investigated if maternal immune activation induces changes in methylation of genes linked to schizophrenia. We found that differentially expressed genes in schizophrenia brain were significantly enriched among MIA induced differentially methylated genes in the foetal brain in a cell-type-specific manner. Upregulated genes in layer V pyramidal neurons were enriched among hypomethylated genes at gestational day 9 (fold change = 1.57, FDR = 0.049) and gestational day 17 (fold change = 1.97, FDR = 0.0006). A linear regression analysis, which showed a decrease in gene expression with an increase in methylation in gestational day 17, supported findings from our enrichment analysis. Collectively, our results highlight a connection between MIA driven methylation changes during gestation and schizophrenia gene expression signatures in the adult brain. These findings carry important implications for early preventative strategies in schizophrenia.

Increased NLRP1 mRNA and Protein Expression Suggests Inflammasome Activation in the Dorsolateral Prefrontal and Medial Orbitofrontal Cortex in Schizophrenia

“…For a recent, comprehensive overview of MIA, refer to [ 76 ], and for a potential mechanistic framework toward a deeper understanding of SZ immunophenotype, see [ 77 ]. As genes overexpressed in SZ brains were significantly enriched among MIA-induced differentially methylated genes in the fetal brain in a cell-type-specific manner (upregulated genes in layer V pyramidal neurons were highly significantly enriched among hypomethylated genes on gestational days 9 and 17), it is believed that MIA-driven methylation changes during gestation may influence SZ gene expression signatures in the adult brain [ 78 ]. MIA can also impact the epigenetic patterns of the genes involved in SZ onset [ 78 ].…”

“…As genes overexpressed in SZ brains were significantly enriched among MIA-induced differentially methylated genes in the fetal brain in a cell-type-specific manner (upregulated genes in layer V pyramidal neurons were highly significantly enriched among hypomethylated genes on gestational days 9 and 17), it is believed that MIA-driven methylation changes during gestation may influence SZ gene expression signatures in the adult brain [ 78 ]. MIA can also impact the epigenetic patterns of the genes involved in SZ onset [ 78 ]. Indeed, it has been shown that inflammation during early development can change the methylation of some genes and alter their expression in adulthood [ 78 , 79 , 80 ].…”

“…MIA can also impact the epigenetic patterns of the genes involved in SZ onset [ 78 ]. Indeed, it has been shown that inflammation during early development can change the methylation of some genes and alter their expression in adulthood [ 78 , 79 , 80 ]. One way of activating inflammatory responses is the activation of the inflammasomes.…”

Neuroinflammation and schizophrenia – is there a link?

“…Steen and colleagues (2023) identified common genetic markers associated with both schizophrenia and systemic immune alterations ( 32 ). MIA can lead to methylation changes in schizophrenia-related genes, thus affecting susceptibility through genetic and environmental risk factors ( 33 , 34 ).…”

“…The first hit arises from MIA and increased inflammation during the fetal and perinatal stages. This initial hit primes the immune system, particularly impacting the microglia, the brain’s primary immune cells responsible for repairing damage and pruning neurons ( 5 , 34 , 43 , 47 ).…”