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Maternal immune activation upregulates the AU020206-IRFs-STAT1 axis in modulating cytokine production in the brain

ABSTRACT: Maternal immune activation (MIA) is reported to increase the risk of psychiatric disorders in the offspring. However, the underlying mechanism remains unclear. Here, we constructed an MIA mouse model by intraperitoneal injection of LPS into pregnant mice and evaluated the behaviors and gene expression profiles in the brains of the female and male offspring, respectively. We found that the MIA female offspring exhibited increased anxiety and a large number of differentially expressed genes (DEGs) in the brain, which were enriched with disease genes of psychiatric disorders and immune functions. In contrast, the MIA male offspring exhibited no significant abnormal behaviors and only a small number of DEGs, which were not enriched with disease genes and immune functions. Therefore, we further pursued the downstream study on the molecular mechanism underlying the increased anxiety in the female offspring. We identified the lncRNA AU020206-IRFs-STAT1-cytokine axis by integrating lncRNA-protein interaction data and TF-promoter interaction data and verified the axis in vitro and in vivo. The female mice with overexpression of AU020206 in the prefrontal cortex exhibited anxiety behaviors. This study illustrates that MIA upregulates the AU020206-IRFs-STAT1 axis in controlling the brain immunity linked to abnormal behaviors, providing a basis for understanding the role of MIA in psychiatric disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE233424 | GEO | 2024/10/09

REPOSITORIES: GEO

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Project description:Maternal stress, anxiety, and depression increase the risk of psychiatric disorders in the progeny. These maternal effects can extend beyond the first generation and affect the grandchildren. In contrast to paternal, maternal effects can impact the offspring not only during gametogenesis, but also through fetal and early-postnatal life, increasing phenotypic complexity and the overall impact. To better understand its non-genetic structure, we dissected a complex maternally-transmitted phenotype to elementary behaviors and their corresponding transmission mechanisms. Chronic stress and depression are associated with reduced serotonin1A receptor (5-HT1AR) levels, and we reported that 5-HT1AR+/- dams transmit anxiety/stress-reactivity traits to their wild-type offspring. Here we show that the maternal effect is propagated to multiple generations, and that the behavioral traits are not transmitted in unison, but rather via parallel and segregated mechanisms, each with generation-dependent penetrance and gender specificity. The ârisk-avoidanceâ and âhypoactivityâ traits of anxiety were transmitted, via a neuro-immune pathway, consecutively from mother to the wild-type F1, F2, and occasionally F3 generation by iterative non-gametic-programming, while the âincreased stress-reactivityâ trait was transmitted to the F2 generation by gametic-programming. Iterative non-gametic-programming of anxiety was linked, via gene expression changes and clustered DNA hypo/hypermethylation at intragenic enhancers, to sphingolipid metabolism and GPCRs in the F1/F2 hippocampus, suggesting dysregulated lipid raft functioning/transmembrane signaling. Conversely, gametic-programming of behavior was predominantly associated with hypomethylation at different promoter-enhancing sequences within a set of genes with diverse neuronal functions. Since differential methylation appeared only postnatally in F2 neurons and was absent in F3 neurons, it is secondary to earlier F2 gametic changes that survive reprogramming in the early embryo, but are erased in F3 germ-cells. Our data introduce parallel and segregated non-genetic transmission of traits as a mechanism that may explain the propagation and pleiotropy of complex behavioral and psychiatric disease phenotypes across generations. Compared three generations of male offspring from wild-type and 5HT1A-R-/+ Swiss Webster mothers with two replicates per sample. Included as well is F2 embryo transfer from wild-type and het parents in wild-type surogates

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Maternal immune activation upregulates the AU020206-IRFs-STAT1 axis in modulating cytokine production in the brain

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