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oai:figshare.com:article/34033807 2026-09-30T16:10:40Z category_4 category_7 category_12 category_13 category_15 category_16 category_19 category_61 category_122 portal_63 item_type_6 month_year_09_2026

Effects of Constitutive Depletion or Excess of Serotonin during Development on the Maturation of Prefrontal Monoaminergic Circuits Marta C. F. Samina (25144831) Maria Stanciu (25144834) Thibault Merkelijn (25144837) Lidiane P. Garcia (25144840) Sabrina Hanswijk (25144843) Josefine S. Witteveen (25144846) Natalia Alenina (135362) Michael Bader (135410) Judith R. Homberg (221999) Sharon M. Kolk (25144849) Biochemistry Medicine Cell Biology Genetics Neuroscience Physiology Pharmacology Developmental Biology Mental Health sup >+</ sup exhibiting localized hyperinnervation critical neuromodulatory morphogen affinity monoamine transporter ht deficiency induced ht clearance pathways cortical scaffold integrity compensatory extracellular 5 cortical scaffold monoamine oxidase wide range uniformly vulnerable suggesting activation structural consequences specific disruption specific alterations selective loss results demonstrate psychiatric disorders neurodevelopmental substrate like signal layer tbr1 ht signaling ht levels ht imbalance ht homeostasis ht dysregulation ht ), heightened sensitivity essential determinant constitutive depletion cognitive phenotypes catecholaminergic fibers afferent innervation 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, <i>Tph2</i> knockout (<i>Tph2</i>^–/–; chronic depletion of 5-HT) and <i>5-HTT</i> knockout (<i>5-HTT</i>^–/–; 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 <i>Slc</i>29<i>a</i>4 and the monoamine oxidase A (<i>Maoa</i>) in <i>5-HTT</i>^–/– 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. 2026-09-30T00:00:00Z Text Journal contribution 10.1021/acschemneuro.6c00382.s001 https://figshare.com/articles/journal_contribution/Effects_of_Constitutive_Depletion_or_Excess_of_Serotonin_during_Development_on_the_Maturation_of_Prefrontal_Monoaminergic_Circuits/34033807 CC BY-NC 4.0