Summary: A new study reports babies born to moms who suffered from viral infections, even mild ones, while pregnant are at increased risk of brain abnormalities.
Babies born to mothers whose immune systems had to grapple with a viral assault — even a mild one — have increased risk of brain and central nervous system abnormalities, according to a new study.
A USC-led team of researchers examined how the immune systems of pregnant mice (roughly equivalent to human mothers in their first trimester) reacted to a chemical that mimics a viral infection akin to the flu. Levels of tryptophan, an amino acid that activates the immune system, increased, causing the placenta to produce more serotonin, which led to higher concentrations of serotonin in the fetal brain.
Previous studies have linked viral-based inflammation during pregnancy and the risk for developmental disorders such as autism, cognitive delay and schizophrenia in offspring, according to the study.
“Serotonin is very important for fetal brain development and can modulate the way the fetal brain is wired,” said Alexandre Bonnin, senior author and an assistant professor of cell and neurobiology at the Keck School of Medicine of USC. “In response to boosted serotonin levels coming from the placenta, the fetal brain stunted its own genesis of serotonin neurons, probably because receptors sensed there was too much serotonin in there. That can be a problem, especially when it leads to the front of the brain being not developed as much as it should be.”
The study was published in The Journal of Neuroscience on June 1. It looked at fetal axon development, that is the growth of “wires” that are necessary for communication between neurons. The mice in the control group received a saline solution instead of the chemical viral-mimic.
The study provides a new molecular pathway to understanding how prenatal insults could program a baby to eventually develop mental diseases. Even mild viral attacks such as the flu or Zika virus, which generally does not require a mother to visit to the doctor’s office, might affect the development of a baby’s central nervous system, said Bonnin, who is based at USC’s Zilkha Neurogenetic Institute.
Zika virus was outside the scope of this study, but Bonnin said ongoing research investigates if serotonin has anything to do with Zika virus and its related neurodevelopmental problems.
In this study, scientists administered a drug to inhibit the activity of an enzyme that produces serotonin via increased tryptophan levels. They blocked excess serotonin production in the placenta, which appeared to normalize fetal forebrain development.
Viral infections and inflammation during pregnancy do not guarantee central nervous system malfunctions in children, Bonnin said. Many times, the health of babies is not impacted. Bonnin referenced another study to explain.
“In the first trimester of pregnancy, if the mom gets an infection such as the flu, the risk of the baby developing schizophrenia 15 years later is increased by approximately threefold,” he said. “It doesn’t mean that if the mom has the flu, the kid will systematically have schizophrenia, but the risk is increased by threefold.”
Funding: The study was supported by the U.S. Department of Defense, the National Institute of Mental Health, the Autism Science Foundation and the Rose Hills Foundation.
Source: Zen Vuong – USC
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain” by Nick Goeden, Juan Velasquez, Kathryn A. Arnold, Yen Chan, Brett T. Lund, George M. Anderson, and Alexandre Bonnin in The Journal of Neuroscience. Published online June 1 2016 doi:10.1523/JNEUROSCI.2534-15.2016
Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain
Maternal inflammation during pregnancy affects placental function and is associated with increased risk of neurodevelopmental disorders in the offspring. The molecular mechanisms linking placental dysfunction to abnormal fetal neurodevelopment remain unclear. During typical development, serotonin (5-HT) synthesized in the placenta from maternal L-tryptophan (TRP) reaches the fetal brain. There, 5-HT modulates critical neurodevelopmental processes. We investigated the effects of maternal inflammation triggered in midpregnancy in mice by the immunostimulant polyriboinosinic-polyribocytidylic acid [poly(I:C)] on TRP metabolism in the placenta and its impact on fetal neurodevelopment. We show that a moderate maternal immune challenge upregulates placental TRP conversion rapidly to 5-HT through successively transient increases in substrate availability and TRP hydroxylase (TPH) enzymatic activity, leading to accumulation of exogenous 5-HT and blunting of endogenous 5-HT axonal outgrowth specifically within the fetal forebrain. The pharmacological inhibition of TPH activity blocked these effects. These results establish altered placental TRP conversion to 5-HT as a new mechanism by which maternal inflammation disrupts 5-HT-dependent neurogenic processes during fetal neurodevelopment.
SIGNIFICANCE STATEMENT The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.
“Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain” by Nick Goeden, Juan Velasquez, Kathryn A. Arnold, Yen Chan, Brett T. Lund, George M. Anderson, and Alexandre Bonnin in The Journal of Neuroscience. Published online June 1 2016 doi:10.1523/JNEUROSCI.2534-15.2016