期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 22, 页码 6041-6049出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2534-15.2016
关键词
inflammation/infection; neurodevelopment; placenta; prenatal programming; serotonin; tryptophan
资金
- US Department of Defense [AR120066]
- Conte Center [P50 MH096972, P50 MH103222]
- Autism Science Foundation
- Rose Hills Foundation
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 mid-pregnancy 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.
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