Neurodevelopmental disorders (NDDs), including autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), and schizophrenia, are associated not only with genetic factors but also with environmental influences during pregnancy. One such factor is maternal viral infection, which can activate the immune system and affect fetal brain development.
Researchers from Italy and the United States investigated how maternal immune activation during pregnancy alters microglial function in the developing fetus. Microglia are the immune cells of the brain that regulate neuronal circuit formation and support normal nervous system maturation during development.
The researchers administered poly(I:C), a molecule that mimics viral infection, to pregnant mice. Maternal immune activation caused widespread changes in gene expression in both microglia and excitatory hippocampal neurons of the offspring. These changes were accompanied by impaired synaptic function, reduced expression of the microglial receptor TREM2, and loss of a microglial subpopulation responsive to type I interferons (IFN-I). Disruption of IFN-I signaling during pregnancy appears to underlie TREM2 dysregulation and the associated synaptic abnormalities.
The relevance of these findings was supported by analyses of postmortem brain tissue from patients with schizophrenia. These individuals also exhibited weakened IFN-I responses and reduced expression of IFN-related genes, mirroring the changes observed in the mouse model of NDD.
Maternal Immune Activation Disrupts Synapse Development in Offspring
The researchers modeled viral infection during pregnancy by administering poly(I:C) to pregnant mice. This triggered a robust antiviral immune response, activating the IFN-I signaling pathway in both mothers and embryos.
In offspring, these changes disrupted the development of excitatory synapses in the hippocampus. Early in development, synaptic density was increased, but it later declined significantly, whereas inhibitory synapses and neuronal numbers remained unchanged. In adulthood, differences in excitatory synapse numbers were no longer detectable, suggesting a transient disturbance during a critical period of brain development.
Blocking maternal IFN-I signaling before poly(I:C) administration prevented excitatory synapse loss and completely restored their function in offspring. These findings indicate that excessive activation of IFN-I signaling plays a central role in synaptic developmental abnormalities.
Maternal IFN-I Responses Regulate TREM2 Levels Independently of Microglial Phagocytic Dysfunction
Although microglial numbers remained unchanged, maternal immune activation altered microglial phagocytic activity. Early in development, microglia showed increased engulfment of synaptic material, whereas this capacity declined later.
At the same time, offspring exhibited reduced expression of the microglial receptor TREM2 and elevated levels of soluble TREM2 (sTREM2) in the blood. Blocking maternal IFN-I signaling prevented these changes and restored TREM2 expression but did not correct abnormalities in microglial phagocytic activity.
TREM2 Links Maternal Immune Activation to Synaptic and Behavioral Abnormalities
The researchers analyzed hippocampal cells from offspring following maternal immune activation and found that poly(I:C) did not alter overall brain cell composition but significantly changed gene expression in excitatory neurons. These changes involved genes associated with synaptic organization, schizophrenia, bipolar disorder, and autism spectrum disorder.
Most of these abnormalities depended on TREM2; in offspring expressing TREM2, maternal immune activation reduced excitatory synapse density in the hippocampus. In contrast, TREM2-deficient offspring did not develop these abnormalities, and synapse density remained elevated regardless of poly(I:C) exposure.
As adults, offspring exposed to maternal immune activation displayed increased anxiety-like behavior and exaggerated startle responses, traits associated with schizophrenia. These behavioral abnormalities were absent in TREM2-deficient mice.
TREM2 Determines Microglial Alterations Following Maternal Immune Activation
Maternal immune activation reduced TREM2 expression in offspring microglia and impaired their ability to eliminate excess synapses. In addition, microglia showed decreased expression of genes involved in antiviral immunity, IFN-I signaling, and cytokine responses.
Most of these changes depended on TREM2. In its absence, poly(I:C)-induced abnormalities in gene expression and microglial function were substantially attenuated.
TREM2 Is Required for Normal Microglial Responses to Type I Interferons
Analysis of microglial populations identified several functional states, including an IFN-I-responsive microglial subpopulation. Following maternal immune activation, both the abundance of these cells and the expression of associated genes were significantly reduced in offspring. Microglia also became less efficient at clearing dying neurons, indicating impaired protective functions.
These alterations were absent in TREM2-deficient mice. Instead, expression of IFN-I response genes remained elevated after poly(I:C) exposure.
Excessive Maternal IFN-I Signaling Disrupts Microglial IFN-I Responses Through CDK8 and STAT1
Maternal immune activation reduced the expression of IFN-response genes in offspring microglia. Blocking maternal IFN-I signaling fully restored levels of STAT1, a key regulator of IFN responses.
In addition, offspring exposed to poly(I:C) showed increased activity of the CDK8–STAT1 signaling pathway. CDK8 activates STAT1, and together they regulate IFN-I-mediated antiviral responses. Blocking maternal IFN-I signaling normalized both CDK8 expression and STAT1 activation.
Impaired IFN-I Responses in Patients With Schizophrenia
Gene expression changes identified in microglia and neurons from mice exposed to maternal immune activation significantly overlapped with genes associated with human neurodevelopmental disorders, including schizophrenia, autism, ADHD, epilepsy, and intellectual disability.
Analysis of brain tissue from patients with schizophrenia revealed similar findings. These patients exhibited reduced expression of genes involved in immune processes, inflammatory responses, and antiviral defense, including genes within the type I interferon signaling pathway. Although expression of TREM2 and TYROBP was unchanged, researchers identified pronounced alterations in TREM1L, a gene associated with the TREM2 signaling pathway. CDK8 levels were also elevated, mirroring observations in the mouse NDD model.
Conclusion
Although poly(I:C) does not cross the placenta, the surge of cytokines and type I interferons it induces can alter developmental programs in fetal microglia and neurons. These disturbances may result from long-lasting changes in gene expression. Consequently, microglia may retain a form of “immune memory” of early-life immune activation, leading to persistent functional abnormalities, altered TREM2 expression, and impaired neural circuit formation even after IFN-I levels return to normal.
Controlling type I interferon responses during pregnancy and using anti-inflammatory therapies during viral infections may help reduce the risk of neurodevelopmental disorders in offspring. After birth, activation of the TREM2 signaling pathway may represent a promising therapeutic approach by supporting microglial function and promoting normal neural circuit development.
