Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain
Open accessAbstract
In addition to its role in neurotransmission, embryonic serotonin (5-HT) has been implicated in the regulation of neurodevelopmental processes. For example, we recently showed that a subset of 5-HT1-receptors expressed in the fetal forebrain mediate a serotonergic modulation of thalamocortical axons response to axon guidance cues, both in vitro and in vivo. This influence of 5-HT signaling on fetal brain wiring raised important questions regarding the source of the ligand during pregnancy. Until recently, it was thought that 5-HT sources impacting brain development arose from maternal transport to the fetus, or from raphe neurons in the brainstem of the fetus. Using genetic mouse models, we uncovered previously unknown differences in 5-HT accumulation between the fore- and hindbrain during early and late fetal stages, through an exogenous source of 5-HT. Using additional genetic strategies, a new technology for studying placental biology ex vivo, and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor, in both mice and humans. These results implicate a new, direct role for placental metabolic pathways in modulating fetal brain development and suggest an important role for maternal-placental-fetal interactions and 5-HT in the fetal programming of adult mental disorders.
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Serotonergic projections from the dorsal and medial Raphe nuclei are among the first to emerge and arrive in the PFC around E16/E17 in rodents and postnatal weeks 10-13 in humans.
“The brain matures from the brainstem to the more frontal cortical regions, and it is therefore not surprising that serotonergic projections from both the dorsal as well as the medial Raphe nuclei (DRN, MRN respectively) are among the first to emerge and are set towards cortical regions where they arrive in the PFC around E16/E17 in rodent and week postnatal 10–13 in humans [113–116].”
From Development of prefrontal cortex (2022) · cites this paper as [114]
Section 1, “Role of 5-HT in fetal forebrain wiring” (page unavailable), describes early dorsal-raphe neurons and axons reaching rostral mouse regions, including the neocortex, by E14.5. Section 2, “Sources of 5-HT in the fetal forebrain” (page unavailable), places large numbers of raphe axons in the forebrain around E16.5. Neither passage establishes projections from the median raphe, arrival specifically in the PFC at E16/E17, or the stated timing in humans. (LLM, conf=0.87)
Experimental — accuracy not yet measuredExternal neurotransmitter sources, such as the placenta, can play a role in the early shaping of cortical areas.
“External neurotransmitter sources, such as the placenta, can play a role in this early shaping of cortical areas [114, 118, 241, 242].”
From Development of prefrontal cortex (2022) · cites this paper as [114]
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- Authors
- Bonnin, A., & Levitt, P.
- Affiliations
- University of Southern California (US)
- ORCID
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 197
- Pages
- 1-7
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC3225275
- OpenAlex
- W2069368314
- Cited by
- 311
- References
- 43
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 23 · 2023: 24 · 2022: 25 · 2021: 29 · 2020: 26 · 2019: 17 · 2018: 18 · 2017: 21 · 2016: 20 · 2015: 21 · 2014: 19 · 2013: 19 · 2012: 16
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NICHD (5R21HD065287)
- NARSAD
- NIMH (1P50MH078280A1)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- serotonin, fetal brain development, placenta, tryptophan metabolism, 5-HT1 receptors
- MeSH terms
- Animals, Brain, Female, Fetus, Humans, Placenta, Pregnancy, Serotonin, Fetal Development, Mice, Neurogenesis
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