Time-specific perturbation of the serotonergic system differentially modulates the transcriptional landscape of hippocampal subregions in female rats

Serotonin (5-HT) is implicated in the pathophysiology of psychiatric disorders, and genetic alterations in the serotonin transporter (5-HTT) are identified as risk factors for increased vulnerability. Beyond its role as a neurotransmitter in the adult brain, 5-HT exerts fundamental functions during early development guiding neuronal maturation and network assembly. Perturbations of serotonergic signaling in these sensitive windows have been associated with long-term changes in brain circuitry and increased susceptibility to psychiatric conditions. The present study aimed to further investigate how the timing of 5-HTT manipulation during perinatal development influences the molecular response, by comparing the effects of transient pharmacological inhibition at specific stages to those seen in constitutive 5-HTT knockout rats. We analyzed transcriptional profiles in the dorsal (dHip) and ventral hippocampus (vHip) of adult females, focusing on pathways relevant to neuroplasticity, microglial activation, microglia-neuron interaction, perineuronal nets, GABAergic signaling, antioxidant and mitochondrial function, and autophagy. Our findings show that both constitutive deletion and pharmacological inhibition of 5-HTT induce long-lasting molecular alterations in the hippocampus, with partly overlapping but also distinct signatures depending on the timing of exposure and the hippocampal subregion. In conclusion, constitutive and time-specific early-life perturbations of serotonergic signaling converge on persistent deficits in hippocampal plasticity, but differ in region- and timing-dependent molecular outcomes. These findings provide a framework to further dissect the mechanisms through which early life serotonergic perturbations shape long-term brain function, offering insights that could guide future research toward more targeted therapeutic approaches.