The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain
Open accessAbstract
UNLABELLED: 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.
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“Recent data from this mouse model also show alterations in CNS and intestinal 5-HT levels which accompany the changes demonstrated in the GI microbiome and ASD-relevant behaviors [75, 76, 77, 78].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [76]
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“3F) show that increasing concentrations of TRP substrate (up to fourfold above the normal physiological concentrations of 60 M; Schröcksnadel et al., 2006) induce a linear increase of 5-HT synthesis.”
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Maternal immune activation and autism spectrum disorder: From rodents to nonhuman and human primates
Careaga, M., Murai, T., & Bauman, M. D. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.10.020 · Cited by 348
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Howell, K. R., & Powell, T. L. (2016) · Reproduction · doi:10.1530/rep-16-0495 · Cited by 370
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The Impact of Systemic Inflammation on Neurodevelopment
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Metadata
- Authors
- Goeden, N., Velasquez, J., Arnold, K. A., Chan, Y., Lund, B. T., Anderson, G. M., & Bonnin, A.
- Affiliations
- University of Southern California (US)
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-06-01
- Volume
- 36
- Issue
- 22
- Pages
- 6041-6049
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4887568
- OpenAlex
- W2409273775
- Cited by
- 264
- References
- 48
- Citations by year
- 2026: 16 · 2025: 28 · 2024: 25 · 2023: 32 · 2022: 31 · 2021: 36 · 2020: 30 · 2019: 20 · 2018: 29 · 2017: 13 · 2016: 4
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- University of Southern California
- Autism Science Foundation
- Rose Hills Foundation
- National Institute of Mental Health (P50MH103222, P50MH096972)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD065287)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- maternal inflammation, fetal brain development, placenta, serotonin, tryptophan metabolism, tryptophan hydroxylase, poly(I:C), neurodevelopmental disorders, placental insufficiency, prenatal immune challenge
- MeSH terms
- Animals, Brain, Disease Models, Animal, Female, Fetal Diseases, 5-Hydroxytryptophan, Inflammation, Fenclonine, Placenta, Polydeoxyribonucleotides, Pregnancy, Prenatal Exposure Delayed Effects, Serotonin, Serotonin Antagonists, Cytokines, Gene Expression Regulation, Developmental, Statistics, Nonparametric, Fetal Development, Mice
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