Cited by 264Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsMaternal Mental Health During Pregnancy and Postpartum

Maternal inflammation disrupts fetal neurodevelopment via increased placental output of serotonin to the fetal brain

Open access
Goeden, Nick, Velasquez, Juan, Arnold, Kathryn A., Chan, Yen, Lund, Brett T., Anderson, George M., Bonnin, Alexandre·2016·The Journal of Neuroscience

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1523/jneurosci.2534-15.2016

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MIA mice show alterations in CNS and intestinal 5-HT levels that accompany changes in the GI microbiome and ASD-relevant behaviors.

    “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].”

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

1 of the 48 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

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
Published
2016-06-01
Volume
36
Issue
22
Pages
6041-6049
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review