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 Tph2 GFP 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 raphe 5-HT neurons, arguing against potential fluoxetine-mediated down-regulation of the Tph2 promoter driving GFP expression in the Tph2 GFP mouse model. In keeping with this notion, mice bearing the pan-serotonergic driver Pet1-Cre 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.

Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression

“…In agreement with our findings, chronic (4-wk) FLX but not desipramine treatment of normal adult rats increases SERT+ axons and their branching in piriform cortex and NAc, although behavioral improvement was not tested 59 . Oppositely, in normal adult mice chronic FLX reduced the density of hippocampal 5-HT innervation 60 . Interestingly, we did not see changes in 5-HT projections in these regions in our mouse PSD model 35 .…”

1,25(OH)2D3 attenuates sleep disturbance in mouse models of Lewis lung cancer, in silico and in vivo

“…Our results indicated 1,25(OH) 2 D 3 obviously influenced the expression of TPH2 in the hippocampus, this may be due to special advantages of the hippocampus. Genetic depletion of 5-HT dramatically increases the serotonergic density of fiber in the hippocampus, and genetic inactivation of TPH2 causes selective inactivation of 5-HT, resulting in an altered density of 5-HT fibers within various targets, and the hippocampus shows the highest level of plasticity (Nazzi et al, 2019). According to the experimental results, we found that BDNF and 5-HT were crucial to hippocampal neurogenesis and related to sleep modulation.…”

“…Following nerve lesions, astrocytes are activated, which induces increased GFAP expression (Nazzi et al, 2019). Protein of GFAP was significantly upregulated in tumor-bearing mice, which implied astrocytes become activated, as classically characterized by hypertrophied morphology, and subsequently resulted in neuroinflammation and nitroxidative stress, neuronal and glial cells losses, and caused a significant decrease of BDNF (Berger et al, 2011).…”

Slitrk2 deficiency causes hyperactivity with altered vestibular function and serotonergic dysregulation

“…Because the serotonergic neurons in raphe nuclei send their axons widely as early as late embryonic stages, the cell number reduction may have profound effects on the establishment of local serotonergic signaling. It is known that the hippocampal serotonergic fibers are shaped in response to subtle changes of serotonin homeostasis ( Nazzi et al., 2019 ). As to the hippocampus of Slitrk2 KO mice, serotonin and its metabolite were increased together with the increased density of the serotonergic fibers at CA3.…”