Fetal brain development can be negatively impacted by an infection that occurs in utero, and the resulting maternal inflammation. Indeed, an illness in a mother is associated with an increased risk of neuropsychiatric disorders in affected offspring, even in the absence of a brain infection in a fetus. However, the cell types that mediate the fetus’s response to maternal inflammation are largely unknown.

Now, scientists show that immune reactions in pregnant mice are detected in the developing embryo by microglia—the phagocytes of the brain—that express receptors for pathogens and cytokines throughout embryonic development. The study provides new insights into how the maternal immune response might influence brain development in embryos.

The work is published in Development in the paper, “Fetal brain response to maternal inflammation requires microglia.”

A research team led by Paola Arlotta, PhD, chair of the department of stem cell and regenerative biology at Harvard University, used a rodent maternal immune activation (MIA) model in which polyinosinic:polycytidylic acid is injected into pregnant mice to stimulate an immune response without causing an actual infection.

The response of cells in the embryonic brain were characterized by assessing gene expression. Using this approach, the scientists showed that microglia can sense the maternal immune response. “Microglia are the immune cells of the brain. They play a critical role during inflammation and infection and also have fundamental functions in healthy brain development,” explained Arlotta.

Following the mother’s immune response, embryonic microglia alter their gene expression. This also occurs in the surrounding neurons. Interestingly, the change of gene regulation in neighboring cells depends on microglia being present in the brain. When the researchers repeated the experiments using mice with a selective genetic deletion of microglia, other brain cells did not react to the maternal immune response. According to the authors, this indicates that “microglia are required for the transcriptional response of other cortical cell types to MIA.”

Many viral infections are short-lived. However, the changes caused by the maternal immune system, in embryonic brain cells, persist well after the immune reaction has subsided. “Based on previous studies demonstrating that microglia exposed to early infections respond differently to stimuli in adulthood, we hypothesized that the maternal immune response could induce changes in microglial gene regulation that persist postnatally” said Bridget Ostrem, MD, PhD, assistant professor of neurology at the University of California, San Francisco.

“Our results suggest a potential role for microglia as therapeutic targets in the setting of maternal infections,” Ostrem asserted.

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