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.
Overview
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.
Integrity signals
Registry
Cites
Statistics
Verification
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.
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?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
Prevention of Allogeneic Fetal Rejection by Tryptophan Catabolism
Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I. E., Conway, S. J., Marshall, B., Brown, C. C., & Mellor, A. L. (1998) · Science · doi:10.1126/science.281.5380.1191 · Cited by 2,589
The developmental role of serotonin: news from mouse molecular genetics
Gaspar, P., Cases, O., & Maroteaux, L. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1256 · Cited by 1,297
Immune involvement in schizophrenia and autism: Etiology, pathology and animal models
Patterson, P. H. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.12.016 · Cited by 766
Prenatal Poly(I:C) Exposure and Other Developmental Immune Activation Models in Rodent Systems
Meyer, U. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.011 · Cited by 626
A transient placental source of serotonin for the fetal forebrain
Bonnin, A., Goeden, N., Chen, K., Wilson, M. L., King, J., Shih, J. C., Blakely, R. D., Deneris, E. S., & Levitt, P. (2011) · Nature · doi:10.1038/nature09972 · Cited by 608
Self-citationMonitoring tryptophan metabolism in chronic immune activation
Schröcksnadel, K., Wirleitner, B., Winkler, C., & Fuchs, D. (2006) · Clinica Chimica Acta · doi:10.1016/j.cca.2005.06.013 · Cited by 551 · cited 2×
“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.”
BackgroundTowards an immuno-precipitated neurodevelopmental animal model of schizophrenia
Meyer, U., Feldon, J., Schedlowski, M., & Yee, B. K. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.10.012 · Cited by 494
Lidov, H. G. W., & Molliver, M. E. (1982) · Brain Research Bulletin · doi:10.1016/0361-9230(82)90077-6 · Cited by 483
Giovanoli, S., Engler, H., Engler, A., Richetto, J., Voget, M., Willi, R., Winter, C., Riva, M. A., Mortensen, P. B., Feldon, J., et al. (2013) · Science · doi:10.1126/science.1228261 · Cited by 459
Kynurenine is an endothelium-derived relaxing factor produced during inflammation
Wang, Y., Liu, H., McKenzie, G. A., Witting, P. K., Stasch, J., Hahn, M. G., Changsirivathanathamrong, D., Wu, B. J., Ball, H. J., Thomas, S. R., et al. (2010) · Nature Medicine · doi:10.1038/nm.2092 · Cited by 446
Romero, R. J., Miranda, J., Chaemsaithong, P., Chaiworapongsa, T., Kusanovic, J. P., Dong, Z., Ahmed, A. I., Shaman, M., Lannaman, K., Yoon, B. H., et al. (2014) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.3109/14767058.2014.958463 · Cited by 445
Positive Screening for Autism in Ex-preterm Infants: Prevalence and Risk Factors
Limperopoulos, C., Bassan, H., Sullivan, N. R., Soul, J. S., Robertson, R. L., Moore, M., Ringer, S. A., Volpe, J. J., & du Plessis, A. J. (2008) · PEDIATRICS · doi:10.1542/peds.2007-2158 · Cited by 416
Development of the serotonergic system in the rat embryo: An immunocytochemical study
Wallace, J. A., & Lauder, J. M. (1983) · Brain Research Bulletin · doi:10.1016/0361-9230(83)90144-2 · Cited by 402
Serotonin: a regulator of neuronal morphology and circuitry
Daubert, E. A., & Condron, B. G. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.05.005 · Cited by 326
Bonnin, A., & Levitt, P. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.10.005 · Cited by 311
Brummelte, S., Mc Glanaghy, E., Bonnin, A., & Oberlander, T. F. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2016.02.037 · Cited by 306
Maternal infection: window on neuroimmune interactions in fetal brain development and mental illness
Patterson, P. H. (2002) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(02)00299-4 · Cited by 269
Meyer, U., & Feldon, J. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.009 · Cited by 258
Elovitz, M. A., Brown, A. G., Breen, K. E., Anton, L., Maubert, M. E., & Burd, I. D. (2011) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2011.02.011 · Cited by 254
Serotonin modulates the response of embryonic thalamocortical axons to netrin-1
Bonnin, A., Torii, M., Wang, L., RAKIC, P. T., & Levitt, P. R. (2007) · Nature Neuroscience · doi:10.1038/nn1896 · Cited by 249
Winter, C., Djodari-Irani, A., Sohr, R., Morgenstern, R., Feldon, J., Juckel, G., & Meyer, U. (2009) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145708009206 · Cited by 242
Girard, S., Tremblay, L., Lepage, M., & Sébire, G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903349 · Cited by 220
Coan, P. M., Vaughan, O. R., Sekita, Y., Finn, S. L., Burton, G. J., Constancia, M., & Fowden, A. L. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2009.181214 · Cited by 199
Coan, P. M., Angiolini, E., Sandovici, I., Burton, G. J., Constância, M., & Fowden, A. L. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.156133 · Cited by 194 · cited 1×
“Because the maternal blood compartment represents 30% of the placental volume (Coan et al., 2008, 2010), these data suggest that the maternal TRP, but not 5-HT, blood level is increased 24 h after poly(I:C) injection.”
BackgroundHervé, C., Beyne, P., Jamault, H., & Delacoux, E. (1996) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/0378-4347(95)00341-x · Cited by 186
Effects of intrauterine inflammation on developing rat brain
Bell, M. J., & Hallenbeck, J. M. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10423 · Cited by 182
Lipopolysaccharide Sensitizes Neonatal Hypoxic-Ischemic Brain Injury in a MyD88-Dependent Manner
Wang, X., Stridh, L., Li, W., Dean, J. M., Elmgren, A., Gan, L., Eriksson, K., Hagberg, H., & Mallard, C. E. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900762 · Cited by 171
Enayati, M., Solati, J., Hosseini, M.-H., Shahi, H.-R., Saki, G., & Salari, A. A. (2011) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.08.015 · Cited by 152
Seong, H. S., Lee, S. E., Kang, J. H., Romero, R. J., & Yoon, B. H. (2008) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2008.06.040 · Cited by 141
Du, M., Guo, P.-F., Piao, H., Wang, S., Sun, C., Jin, L., Yu, T., Li, Y., Zhang, D., Zhu, R., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1203425 · Cited by 135
Tryptophan catabolism prevents maternal T cells from activating lethal anti-fetal immune responses
Mellor, A. L., & Munn, D. H. (2001) · Journal of Reproductive Immunology · doi:10.1016/s0165-0378(01)00118-8 · Cited by 127
Increased CXCL8 (IL-8) expression in Multiple Sclerosis
Lund, B. T., Ashikian, N., Ta, H. Q., Chakryan, Y., Manoukian, K., Groshen, S. G., Gilmore, W., Cheema, G. S., Stohl, W., Burnett, M. E., et al. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.06.008 · Cited by 124
Lin, Y., Lin, S., & Wang, S. Z. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.12.003 · Cited by 109
Reduced ventricular proliferation in the foetal cortex following maternal inflammation in the mouse
Stolp, H. B., Turnquist, C., Dzięgielewska, K. M., Saunders, N. R., Anthony, D. C., & Molnár, Z. (2011) · Brain · doi:10.1093/brain/awr237 · Cited by 74
Insights into the complex influence of 5‐HT signaling on thalamocortical axonal system development
van Kleef, E. S. B., Gaspar, P., & Bonnin, A. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.8096.x · Cited by 64
Pregnancy and autoimmunity: Maternal treatment and maternal disease influence on pregnancy outcome
Tincani, A., Rebaioli, C. B., Frassi, M., Taglietti, M., Gorla, R., Cavazzana, I., Faden, D., Taddei, F., Lojacono, A., Motta, M., et al. (2005) · Autoimmunity Reviews · doi:10.1016/j.autrev.2005.03.001 · Cited by 55
Infection-Related Morbidities in the Mother, Fetus and Neonate
Bergström, S. (2003) · Journal of Nutrition · doi:10.1093/jn/133.5.1656s · Cited by 46
Janušonis, S., Anderson, G. M., Shifrovich, I., & RAKIC, P. T. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04150.x · Cited by 45
Goeden, N., & Bonnin, A. (2012) · Nature Protocols · doi:10.1038/nprot.2012.144 · Cited by 44
Verhaagh, S., Barlow, D. P., & Zwart, R. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(00)00510-4 · Cited by 39
Placenta-derived hypo-serotonin situations in the developing forebrain cause autism
Sato, K. (2013) · Medical Hypotheses · doi:10.1016/j.mehy.2013.01.002 · Cited by 34
Omer, S. B., & Beigi, R. H. (2016) · JAMA · doi:10.1001/jama.2016.2237 · Cited by 34
THE 5‐HYDROXYTRYPTAMINE CONTENT OF THE PLACENTA AND FOETUS DURING PREGNANCY IN MICE
Robson, J. M., & Senior, J. (1964) · British Journal of Pharmacology and Chemotherapy · doi:10.1111/j.1476-5381.1964.tb02043.x · Cited by 33
Буткевич, И. П., Хожай, Л. И., Михайленко, В. А., & Otellin, V. A. (2003) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-1-96 · Cited by 30
Shayda, H., Mahmood, J.-T., Torkabadi, E., Ghassemi, J., Ensieh, K. S. G., Parivash, D., Leila, B. Y., Mehdi, A. M., & Hassan, Z. A. (2009) · Europe PMC (PubMed Central) · Cited by 15
Cited by
Sorted by citations
Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development
Yockey, L. J., & Iwasaki, A. (2018) · Immunity · doi:10.1016/j.immuni.2018.07.017 · Cited by 588
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
Effects of maternal obesity on placental function and fetal development
Howell, K. R., & Powell, T. L. (2016) · Reproduction · doi:10.1530/rep-16-0495 · Cited by 370
Dietary Inflammatory Index and Non-Communicable Disease Risk: A Narrative Review
Phillips, C. M., Chen, L., Heude, B., Bernard, J. Y., Harvey, N. C., Duijts, L., Mensink‐Bout, S. M., Polańska, K., Mancano, G., Suderman, M. J., et al. (2019) · Nutrients · doi:10.3390/nu11081873 · Cited by 361
The Impact of Systemic Inflammation on Neurodevelopment
Jiang, N. M., Cowan, M. N., Moonah, S. N., & Petri, W. A. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.06.008 · Cited by 343
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
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
