Abstract
Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB.
Highlights
Depression is a complex and heterogeneous neuropsychiatric disorder with a high prevalence and incidence[1]
Data indicate that fluoxetine can directly induce the phosphorylation of tropomyosin receptor kinase B (TrkB) even in the absence of 5-HTT, suggesting that this effect could be independent of 5-HT reuptake blockade[25] or even of a 5-HT surge, since in 5-Htt null mice, extracellular 5-HT levels measured by microdialysis were unchanged in the hippocampus after fluoxetine administration[26]
In order to validate the acute effect of fluoxetine on Bdnf expression, we used primary cortical neurons from Swiss CD1 mouse strain
Summary
Depression is a complex and heterogeneous neuropsychiatric disorder with a high prevalence and incidence[1]. Chronic fluoxetine treatment is known to promote neuroplasticity, hippocampal neurogenesis, by inducing cell proliferation, enhancing newborn cell survival, and accelerating neuronal maturation An increase in both dendritic arborization and length has been observed in the dentate hippocampus after fluoxetine[14,15,16]. We aimed to further dissect the mechanisms of action of fluoxetine on plasticity to better understand to which extent 5-HTT and TrkB/BDNF signaling interact in mediating the neuroplastic effects of this antidepressant. To this aim, we performed both in vitro and in vivo experiments using wild-type (WT) and 5-Htt constitutive KO28 mice to investigate the effects of fluoxetine on markers of neuroplasticity
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