Fluoxetine Induces Morphological Rearrangements of Serotonergic Fibers in the Hippocampus

Abstract

Serotonin (5-HT)-releasing fibers show substantial structural plasticity in response to genetically induced changes in 5-HT content. However, whether 5-HT fibers appear malleable also following clinically relevant variations in 5-HT levels that may occur throughout an individual's life has not been investigated. Here, using confocal imaging and 3D modeling analysis in <i>Tph2</i>^<i>GFP</i> knock-in mice, we show that chronic administration of the antidepressant fluoxetine dramatically affects the morphology of 5-HT fibers innervating the dorsal and ventral hippocampus resulting in a reduced density of fibers. Importantly, GFP fluorescence levels appeared unaffected in the somata of both dorsal and median <i>raphe</i> 5-HT neurons, arguing against potential fluoxetine-mediated down-regulation of the <i>Tph2</i> promoter driving GFP expression in the <i>Tph2</i>^<i>GFP</i> mouse model. In keeping with this notion, mice bearing the pan-serotonergic driver <i>Pet1-Cre</i> partnered with a Cre-responsive tdTomato allele also showed similar morphological alterations in hippocampal 5-HT circuitry following chronic fluoxetine treatment. Moreover 5-HT fibers innervating the cortex showed proper density and no overt morphological disorganization, indicating that the reported fluoxetine-induced rearrangements were hippocampus specific. On the whole, these data suggest that 5-HT fibers are shaped in response to subtle changes of 5-HT homeostasis and may provide a structural basis by which antidepressants exert their therapeutic effect.