Posted August 30, 2016
Alexandre Bonnin, Ph.D., University of Southern California, Los Angeles
Growing evidence derived from epidemiological human data and both in vitro and in vivo animal studies suggests that inflammation resulting from maternal infection during pregnancy results in an increased predisposition for offspring to develop mental disabilities, including autism. Previous research suggests that maternal immune inflammation can adversely affect placental function essential to fetal brain development, but the causal genetic and molecular mechanisms are still unknown. To shed light on metabolic pathway changes resulting from prenatal maternal inflammation that adversely impact fetal brain development, Dr. Alexandre Bonnin, supported by a fiscal year 2012 Autism Research Program Idea Development Award, investigated the role of placental tryptophan hydroxylase 1 (TPH1) pathway in this process.
During early pregnancy, the placenta uses the TPH1 pathway to convert tryptophan (an amino acid provided by the maternal blood circulation) to serotonin (5-HT), a factor essential for fetal development. In particular, placental-derived serotonin can access the fetal brain and promote the development of axonal neural circuitry, the communication conduits used to send signals within and outside of the brain. Prior research suggests that the disruption of 5-HT signaling during fetal growth results in long-term neurological and behavioral dysfunctions in offspring.
Dr. Bonnin hypothesized that maternal inflammation could trigger changes to normal placental tryptophan metabolism, leading to adverse effects on fetal neurodevelopment. In a recent The Journal of Neuroscience article, Dr. Bonnin and his team confirmed this hypothesis in an established mouse model of maternal immune activation. His group found that maternal inflammation induced midway through pregnancy led to temporary increases in placental tryptophan conversion to 5-HT via upregulation of tryptophan processing pathways.
The resulting increase in placental 5-HT production boosted the level of 5-HT in fetal tissue, specifically the fetal forebrain. A decrease in serotonergic axonal outgrowth in the fetal forebrain occurred concomitantly with the surge in 5-HT concentration. However, axonal outgrowth in the fetal forebrain was protected by inhibiting THP1 pathway activity in pregnant mice subjected to the immune activation protocol. Together, these results suggest that higher 5-HT levels in the fetal forebrain resulting from maternal inflammation may thwart normal axonal development in this region.
Dr. Bonnin’s research provides critical insight into maternal inflammation-induced alterations in the THP1 tryptophan metabolic pathway that leads to altered fetal brain development, opening a new avenue of research that could one day lead to the discovery of therapeutic targets for the treatment of autism.
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