Impact of fluoxetine-induced change of 5-HT homeostasis on behavior and serotonergic innervation: identification of sensitive periods of plasticity and irreversible developmental critical windows

The serotonergic system shows a high structural plasticity in response to the genetically induced abrogation of 5-HT. Here, using confocal imaging and 3D modeling analysis we first studied whether the serotonergic system responds to 5-HT fluctuations within the peri-physiological range that may occur throughout an individual’s adult life. Subsequently, we investigated on the effects of these 5-HT oscillations during pre- and early post-natal developmental period. In the first study, chronically treating adult Tph2GFP knock-in mice with fluoxetine and subsequently suspending the treatment, we show that fluoxetine causes a reversible effect on mice behavior and also causes a reversible reduction in serotonergic fiber density in the hippocampus. Then we mimic the human fluoxetine intake by treating Tph2GFP female mice throughout the gestation and lactation period until weaning. We investigate the effect of this treatment on adult offspring, demonstrating an increase in anxiety- and depressive-like behavior that confirm the “behavioral paradox” reported in literature. Then we analyze the serotonergic wiring in the offspring hippocampus during post-natal development up to adulthood and aging, showing that fluoxetine treatment affects irreversibly the morphology of 5-HT fibers by reducing the fiber density. Overall, these data show that a change in 5-HT homeostasis that occurs when the nervous system is already formed (adulthood) causes reversible alterations to the serotonergic wiring, whereas if this oscillation occurs during development it irreversibly impacts the serotonergic circuitry and behavior.