Could an immune reaction to a virus cause autism? We still don’t know the answer to that question, but a new study shows that, in mice, infecting a pregnant mother with an artificial virus can spark a chain of events that leads to autism-like disorders in her offspring.
The study, just released on the mBio website, uses mouse models to follow up on previous studies that indicated infecting a mother with any of a wide range of viruses during pregnancy is associated with increased risk for disorders like autism and schizophrenia. In the latest study, De Miranda et al. explored the effects of infection using a totally fabricated double-strand of RNA that mimics a replicating virus.
In pregnant mice, the fake virus inhibited fetal neuronal stem cell replication and population of the superficial layers of the neocortex of the brain by neurons. In terms of behavior, these offspring had impaired locomotor development and once they reached adulthood, they were less able to filter sensory stimuli and make sense of their environment. Sensory impairments like these, called “abnormal sensorimotor gating responses”, are a hallmark of schizophrenia and autism.
To investigate the mechanisms behind these neural effects, the authors followed up with experiments in mice deficient in Toll-like receptor 3 (TLR3), a component of the innate immune system that also plays a pivotal role in development. The offspring of TLR3-deficient pregnant mice exposed to the virus did not have any of the neural problems, indicating a prominent role for TLR3 in the adverse effects that afflicted the wild type offspring. What’s more, a drug can actually head off these effects: pre-treating wild-type dams with a COX inhibitor called caprofen suppresses the inflammatory response of TLR3 to the artificial virus and allows the fetal stem cells to develop normally.
“This work advances the molecular understanding and not just the association,” between infection and neural and behavioral defects, says Christine Biron, Professor of Molecular Microbiology and Immunology at Brown University and member of mBio’s Board of Editors. Biron says the links between certain infectious agents and behavioral disturbances, like influenza and schizophrenia, have been explored, but research that actually addresses the pathways and mechanisms at work is rarer.
Biron cautions that scientists must be very careful about extrapolating results from mouse studies to humans, particularly in studies of behavior, but the idea that a virus could cause an immune response that leads to neural and developmental problems in children is a sobering one and deserves further analysis.
“The next thing they’re going to try to do is figure whether the immune signal is in the mother or the fetus; that’s a very important point,” says Biron.