title: Vortioxetine promotes maturation of dendritic spines in vitro: A comparative study in hippocampal cultures.
abstract: Cognitive dysfunction is prevalent in patients with major depressive disorder (MDD), and cognitive impairments can persist after relief of depressive symptoms. The multimodal-acting antidepressant vortioxetine is an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist at 5-HT1B receptors, an agonist at 5-HT1A receptors, and an inhibitor of the serotonin (5-HT) transporter (SERT) and has pro-cognitive properties. In preclinical studies, vortioxetine enhances long-term potentiation (LTP), a cellular correlate of neuroplasticity, and enhances memory in various cognitive tasks. However, the molecular mechanisms by which vortioxetine augments LTP and memory remain unknown. Dendritic spines are specialized, actin-rich microdomains on dendritic shafts and are major sites of most excitatory synapses. Since dendritic spine remodeling is implicated in synaptic plasticity and spine size dictates the strength of synaptic transmission, we assessed if vortioxetine, relative to other antidepressants including ketamine, duloxetine, and fluoxetine, plays a role in the maintenance of dendritic spine architecture in vitro. We show that vortioxetine, ketamine, and duloxetine induce spine enlargement. However, only vortioxetine treatment increased the number of spines in contact with presynaptic terminals. In contrast, fluoxetine had no effect on spine remodeling. These findings imply that the various 5-HT receptor mechanisms of vortioxetine may play a role in its effect on spine dynamics and in increasing the proportion of potentially functional synaptic contacts.
authors.affiliation: External Sourcing and Scientific Excellence, Lundbeck Research USA, Paramus, NJ 07652, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Waller
authors.affiliation: Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, DK-8000 Aarhus C, Denmark; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, DK-8240 Risskov, Denmark.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Chen
authors.affiliation: External Sourcing and Scientific Excellence, Lundbeck Research USA, Paramus, NJ 07652, USA. Electronic address: wallerjessica14@gmail.com.
authors.forename: Connie
authors.initials: C
authors.lastname: Sánchez
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects*; D000068736:Duloxetine Hydrochloride / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects*; D007649:Ketamine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects; D000078784:Vortioxetine
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D013440:Sulfides; D005473:Fluoxetine; D000078784:Vortioxetine; D007649:Ketamine; D000068736:Duloxetine Hydrochloride
keywords: Antidepressant; Multimodal; Neuroplasticity; Synapsin