Effects of Constitutive Depletion or Excess of Serotonin during Development on the Maturation of Prefrontal Monoaminergic Circuits

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.