Research conducted by the SickKids Research Institute in Toronto and the University of Pennsylvania has revealed significant insights into how maternal immune stress impacts fetal brain development in mice. The study, published in Nature Neuroscience, demonstrates that immune-related gene activity varies by location and cell type across the developing brain, highlighting crucial differences between male and female embryos.
The investigation centered on how maternal immune activation and the depletion of the maternal microbiome altered immune signaling patterns in embryonic mice. It identified that immune molecules such as cytokines, chemokines, and cognate receptors play a vital role in regulating synapse development, cellular communication, and the migration of neural precursor cells during critical stages of brain development.
During normal development, nerve cells are generated in specific regions, migrate to their final destinations, and arrange themselves into distinct layers, particularly in the cortex. The study underscores that disruptions in the maternal immune system and microbiome are linked to abnormal fetal neurodevelopment, affecting neurogenesis, cell fate, and precursor cell migration.
Research Methodology and Findings
The research team employed a technique known as multiplexed error-robust fluorescence in situ hybridization (MERFISH) to assess immune activity in embryonic mouse brains during mid and late gestation. This method allowed for the detailed analysis of how maternal immune activation and microbiome depletion influenced immune signaling patterns.
After filtering data quality, the study analyzed 2.1 million cells, with each cell revealing a median of 511 molecules detected. Notable differences were observed in male embryos from the maternal immune activation and microbiome depletion groups, which exhibited a thicker deep-layer band and a reduced number of dividing cells in a critical growth zone compared to those from saline-treated controls. In contrast, no significant changes were detected in female embryos belonging to the microbiome depletion group.
Adult offspring underwent social interaction tests and open-field assessments between eight and twelve weeks post-birth. Males exposed to maternal immune activation and microbiome depletion displayed altered social behaviors, while the total distance traveled and interaction time remained consistent across groups. Interestingly, the time spent in the center of the open field decreased for males affected by maternal immune stress, although movement speed was comparable across all groups.
Sex-Specific Gene Activity Changes
The study found that gene activity shifted differently in male and female embryos following maternal immune activation. Key genes associated with growth and division in early brain cells, such as Nes and Mki67, decreased in males across various precursor populations. Conversely, male embryos showed an increase in the activity of genes vital for neural development, including Neurod1, Neurod2, and Neurog2, particularly in intermediate precursor cells and dorsal radial precursors. These changes were not observed in female embryos.
The depletion of the maternal microbiome resulted in changes in gene activity that were more aligned across both sexes. Immune-related genes showed increased activity in precursor populations, such as ventral radial precursors and intermediate precursor cells.
A significant mechanism highlighted in this study involves the chemokine CXCL12, which facilitates cell-to-cell communication in the developing brain, and its receptor CXCR7. Both Ackr3, which encodes CXCR7, and Cxcl12 displayed changes in expression following maternal immune activation and microbiome depletion, suggesting a common mechanism linked to neural progenitor abnormalities.
The spatial arrangement of cells within the cortex was also affected. Following maternal immune activation, distances between certain cell populations increased, indicating altered positioning of brain precursor cells and microglia relative to developing neurons. This shift may affect the overall development and connectivity of the brain.
The findings of this study connect maternal immune activation and microbiome depletion with sex-specific alterations in immune gene expression, ligand–receptor signaling, and cell spacing within the embryonic brain. The research suggests that CXCL12 and CXCR7 signaling are critical mediators of abnormal neural differentiation and migration stemming from maternal immune stressors.
Future studies are anticipated to include gain-of-function and loss-of-function experiments to further investigate neuronal migration changes and their implications for later-life behaviors.
This research not only sheds light on the complex interplay between maternal health and fetal brain development but also raises awareness about the potential long-term consequences of maternal immune conditions on offspring. The study emphasizes the need for comprehensive understanding of immune signaling networks to grasp fully the impact of maternal stressors on brain development.
The full study can be found in the article titled, “Spatial transcriptomics of the developing mouse brain immune landscape reveals effects of maternal immune activation and microbiome depletion,” authored by Bharti Kukreja and colleagues.