For years, research has suggested an association between activation of the immune system during pregnancy and an increased risk of neurodevelopmental alterations in offspring, including schizophrenia and autism spectrum conditions. The first evidence of this phenomenon emerged following viral epidemics in the mid-20th century, when children born to infected mothers showed greater susceptibility to certain neuropsychiatric disorders. However, the biological mechanisms linking maternal inflammation and fetal brain development have long remained poorly defined.

A new study published in Neuron helps clarify this picture by identifying a key role for type I interferon (IFN-I), a central molecule in the antiviral response, and microglia, the resident immune cells of the brain that also play a fundamental role in the development of neuronal connections. The results of this preclinical research indicate that maternal immune activation during pregnancy can interfere with communication between neurons and microglia, influencing both synapse formation and the gene expression programs that guide brain maturation, processes that are frequently altered in neurodevelopmental disorders. The research was coordinated by Michela Matteoli – Director of the Neuroscience Program at Humanitas and Full Professor at Humanitas University, and Fabia Filipello, currently a researcher at IRCCS Ospedale Policlinico San Martino in Genoa. The study was conducted by Matteo Bizzotto, with support from other researchers at Humanitas Research Hospital and Humanitas University, including Raffaella Morini, staff scientist in Prof. Matteoli’s laboratory. The research also originated thanks to close collaboration with the laboratory of Prof. Celeste Karch at Washington University in St. Louis, where Fabia Filipello worked for several years.

“Understanding how immune responses during pregnancy may influence fetal brain development is now one of the major challenges in neurobiology,” observes Michela Matteoli. “These findings reinforce the idea that monitoring and studying maternal inflammatory processes more deeply is essential for better understanding the mechanisms underlying certain neurodevelopmental disorders.”

How maternal immune activation influences the developing brain

To investigate these mechanisms, researchers used an experimental model of maternal immune activation (MIA), induced through Poly(I:C), a molecule that mimics viral infection and triggers a strong antiviral response with the production of type I interferons. Starting from this activation in the mother, the study shows how immune signals can indirectly influence fetal brain development. Through single-nucleus transcriptomic analyses, a technique that makes it possible to measure which genes are active in individual cells, researchers observed that this immune response profoundly alters the brain development programs of the offspring. In particular, immune activation does not simply generate a transient inflammatory response, but appears to permanently reorganize the processes regulating synaptic development, namely the formation and maturation of connections between neurons.

“The role of type I interferons was already well known in immunology,” explains Fabia Filipello, “but these data suggest that their activation during pregnancy may have broader consequences for brain development, influencing both microglia and the molecular programs regulating synapse maturation.”

Microglia and TREM2: a disrupted dialogue

One of the most significant findings concerns the involvement of the TREM2 receptor, expressed mainly by microglia. Receptors are proteins located on the cell surface that function as “sensors”: they receive external signals and activate specific responses within the cell. In the case of microglia, TREM2 is essential for regulating their activity during brain development. Indeed, microglia do not only perform immune functions, but also actively participate in brain maturation by eliminating excess or nonfunctional synapses through a process known as phagocytosis.

In the studied model, maternal immune activation is associated with reduced TREM2 expression in offspring. This alteration results in microglia that are less efficient at recognizing and removing cellular elements and synapses that need to be eliminated, thereby compromising the proper balance of synaptic remodeling during development.

Overall, these data indicate that the maternal interferon-mediated immune response can durably influence brain development by altering microglial function and the process of synapse maturation. Consistent with this hypothesis, when maternal interferon signaling is experimentally blocked, both TREM2 expression and normal synaptic physiology are restored, indicating a possible causal role of this biological cascade in the development of the observed alterations.

A bridge between basic research and human biology

To assess the translational relevance of the findings, the team also compared the experimental data with transcriptomic analyses obtained from a brain tissue bank donated for research by individuals affected by schizophrenia. In these samples, researchers identified reduced expression of genes associated with type I interferon responses, a molecular signature consistent with what was observed in the experimental model.

“A particularly important aspect of the study is that the alterations identified in the experimental model also show parallels in human tissues,” comments Matteo Bizzotto. “This does not mean that the mechanism concerns schizophrenia exclusively, but it suggests that alterations in immune responses and microglial function may represent a common vulnerability factor across different neurodevelopmental disorders.”

Overall, the work identifies a biological axis linking maternal interferon, microglia, TREM2, and synapse development, offering new elements for understanding how inflammatory events during pregnancy may influence brain development in offspring. According to the authors, monitoring maternal immune responses and better understanding interferon dynamics could in the future contribute to identifying preventive or therapeutic strategies aimed at reducing the risk of neurodevelopmental alterations in offspring.