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| Item Type: | Article |
|---|---|
| Title: | Effects of constitutive depletion or excess of serotonin during development on the maturation of prefrontal monoaminergic circuits |
| Creators: |
Samina, Marta C.F.  ORCID: https://orcid.org/0009-0002-9766-1333, Stanciu, Maria, Merkelijn, Thibault ORCID: https://orcid.org/0009-0003-7053-7188, Garcia, Lidiane P., Hanswijk, Sabrina, Witteveen, Josefine S., Alenina, Natalia ORCID: https://orcid.org/0000-0002-6071-5433, Bader, Michael ORCID: https://orcid.org/0000-0003-4780-4164, Homberg, Judith R. and Kolk, Sharon M.
|
| Abstract: | Serotonin (5-hydroxytryptamine; 5-HT) is a critical neuromodulatory morphogen-like signal that governs prenatal cortical circuit assembly, and altered 5-HT signaling is implicated in a wide range of psychiatric disorders. Yet the structural consequences of lifelong 5-HT imbalance during the initial blueprinting phase remain poorly defined. Here, we used two genetic rat models representing the extremes of 5-HT homeostasis, Tph2 knockout (Tph2–/–; chronic depletion of 5-HT) and 5-HTT knockout (5-HTT–/–; chronic excess of 5-HT), to investigate sub-region-specific alterations in the embryonic medial prefrontal cortex (mPFC) and in prefrontal monoaminergic circuit maturation. Our results demonstrate that the developing mPFC is not uniformly vulnerable to 5-HT dysregulation. Instead, the prelimbic (PL) cortex emerged as a region of heightened sensitivity to low 5-HT levels, exhibiting localized hyperinnervation of catecholaminergic fibers and an increase in deep-layer Tbr1+ neurons. In contrast, within the infralimbic (IL) cortex, 5-HT deficiency induced a selective loss of reelin (Reln)-producing Cajal-Retzius (CR) cells, indicating a sub-region-specific disruption of the cortical scaffold. Transcriptomic analyses identified selective upregulation of the low-affinity monoamine transporter Slc29a4 and the monoamine oxidase A (Maoa) in 5-HTT–/– embryos, suggesting activation of compensatory extracellular 5-HT clearance pathways during embryogenesis. Together, these findings establish prenatal 5-HT levels as an essential determinant of afferent innervation and cortical scaffold integrity, and suggest that late-gestational developmental blueprinting errors may provide a neurodevelopmental substrate for later monoaminergic circuit dysfunction linked to social and cognitive phenotypes. |
| Keywords: | Neurodevelopment, Medial Prefrontal Cortex (mPFC), Serotonin (5-HT), Serotonin Transporter (5-HTT), Tryptophan Hydroxylase 2 (TPH2), Cajal-Retzius Cells, Animals, Rats |
| Source: | ACS Chemical Neuroscience |
| ISSN: | 1948-7193 |
| Publisher: | American Chemical Society |
| Date: | 30 September 2026 |
| Official Publication: | https://doi.org/10.1021/acschemneuro.6c00382 |
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