Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation
Open accessAbstract
Besides its "classical" neurotransmitter function, serotonin (5-HT) has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system, besides an external placental source, represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection system, originating in the brainstem raphe nuclei, is the medial prefrontal cortex (mPFC), an area involved in higher cognitive functions and important in the etiology of many neurodevelopmental disorders. Little is known, however, about the exact role of 5-HT and its signaling molecules in the formation of the raphe-prefrontal network. Using explant essays, we here studied the role of the 5-HT transporter (5-HTT), an important modulator of the 5-HT signal, in rostral raphe-prefrontal network formation. We found that the chemotrophic nature of the interaction between the origin (rostral raphe cluster) and a target (mPFC) of the 5-HT projection system was affected in rats lacking the 5-HTT (5-HTT(-/-)). While 5-HTT deficiency did not affect the dorsal raphe 5-HT-positive outgrowing neurites, the median raphe 5-HT neurites switched from a strong repulsive to an attractive interaction when co-cultured with the mPFC. Furthermore, the fasciculation of the mPFC outgrowing neurites was dependent on the amount of 5-HTT. In the mPFC of 5-HTT(-/-) pups, we observed clear differences in 5-HT innervation and the identity of a class of projection neurons of the mPFC. In the absence of the 5-HTT, the 5-HT innervation in all subareas of the early postnatal mPFC increased dramatically and the number of Satb2-positive callosal projection neurons was decreased. Together, these results suggest a 5-HTT dependency during early development of these brain areas and in the formation of the raphe-prefrontal network. The tremendous complexity of the 5-HT projection system and its role in several neurodevelopmental disorders highlights the need for further research in this largely unexplored area.
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Serotonin exerts a significant trophic and modulatory function in neurodevelopmental processes such as proliferation, migration, and differentiation in cortical areas, including the PFC.
“It has become widely accepted that serotonin exerts a significant trophic and modulatory function in neurodevelopmental processes such as proliferation, migration and differentiation in cortical areas, including the PFC [119, 123, 125–129].”
From Development of prefrontal cortex (2022) · cites this paper as [128]
The Introduction and Discussion (pages unavailable in our copy) describe serotonin as a neurodevelopmental signal and link altered serotonin input to mPFC cortical layering and neuronal identity. The Discussion raises effects on cortical neuron migration only as a possibility, and the passages do not establish a role in proliferation. Thus the paper supports the broad developmental role but not the full list of processes as stated. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTreatments against maternal depression such as SSRIs can cause substantial structural damage to prefrontal subdomains.
“treatments against maternal depression such as SSRIs can cause substantial structural damage to prefrontal subdomains [125, 128].”
From Development of prefrontal cortex (2022) · cites this paper as [128]
The Results report altered serotonergic innervation across medial prefrontal subareas in rat pups lacking the serotonin transporter. The Introduction discusses SSRIs given during pregnancy, but the study used a genetic knockout rather than maternal SSRI treatment. Its findings do not establish that SSRIs cause substantial structural damage to prefrontal subdomains. (LLM, conf=0.88)
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Development of prefrontal cortex
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“Although maternal stress itself can be detrimental to brain development in general and the developing PFC in particular (for review see [125]), treatments against maternal depression such as SSRIs can cause substantial structural damage to prefrontal subdomains [125, 128].”
BackgroundSelf-citationAbdolmaleky, H. M., Nohesara, S., Ghadirivasfi, M., Lambert, A. W., Ahmadkhaniha, H., Ozturk, S., Wong, C. K., Shafa, R., Mostafavi, A., & Thiagalingam, S. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2013.12.007 · Cited by 102 · see citing works
Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link
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Self-citationGarcia, L. P., Witteveen, J. S., Middelman, A., van Hulten, J. A., Martens, G. J. M., Homberg, J. R., & Kolk, S. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1105-x · Cited by 28 · see citing works
Self-citationEditorial perspective of the Research Topic “Deciphering serotonin's role in neurodevelopment”
Homberg, J. R., Kolk, S. M., & Schubert, D. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00212 · Cited by 26 · see citing works
Self-citationvan de Wijer, L., Garcia, L. P., Hanswijk, S. I., Rando, J., Middelman, A., ter Heine, R., Mast, Q. D., Martens, G. J. M., van der Ven, A. J. A. M., Kolk, S. M., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0420-y · Cited by 13 · see citing works
Self-citationGarcia, L. P., Van de Wijer, L., Hanswijk, S. I., Rando, J., Witteveen, J. S., Middelman, A., ter Heine, R., de Mast, Q., Martens, G. J. M., van der Ven, A. J. A. M., et al. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114050 · Cited by 6 · see citing works
Self-citation
- Authors
- Witteveen, J. S., Middelman, A., van Hulten, J. A., Martens, G. J. M., Homberg, J. R., & Kolk, S. M.
- Affiliations
- Radboud University Nijmegen (NL)
- Donders Institute for Brain, Cognition and Behaviour (NL)
- Corresponding author
- Kolk, Sharon M.
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 7
- Pages
- 143-143
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC3790074
- OpenAlex
- W2121242763
- Cited by
- 53
- References
- 128
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 1 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 5 · 2013: 2
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (433‐09‐311)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- serotonin, serotonin transporter, raphe nuclei, medial prefrontal cortex, brain development, neurite outgrowth, fasciculations, SATB2, callosal projection neurons, neurodevelopmental disorders
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.
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