A critical role of mitochondria in BDNF-associated synaptic plasticity after one-week vortioxetine treatment

TY - JOUR

T1 - A critical role of mitochondria in BDNF-associated synaptic plasticity after one-week vortioxetine treatment

AU - Chen, Fenghua

AU - Danladi, Jibrin

AU - Ardalan, Maryam

AU - Elfving, Betina

AU - Müller, Heidi K

AU - Wegener, Gregers

AU - Sanchez, Connie

AU - Nyengaard, Jens R

PY - 2018

Y1 - 2018

N2 - Background: Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor signaling. Methods: Rats were treated for 1 week with vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria-related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting. Results: Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after vortioxetine treatment. Gene expression levels of Rac1 after vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers. Conclusion: Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following vortioxetine compared with fluoxetine may be ascribed to vortioxetine’s modulation of serotonin receptors.

AB - Background: Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor signaling. Methods: Rats were treated for 1 week with vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria-related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting. Results: Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after vortioxetine treatment. Gene expression levels of Rac1 after vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers. Conclusion: Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following vortioxetine compared with fluoxetine may be ascribed to vortioxetine’s modulation of serotonin receptors.

KW - BDNF

KW - Depression

KW - Mitochondria

KW - Synapse

KW - Vortioxetine

UR - http://www.scopus.com/inward/record.url?scp=85055689982&partnerID=8YFLogxK

U2 - 10.1093/ijnp/pyy022

DO - 10.1093/ijnp/pyy022

M3 - Journal article

C2 - 29514282

SN - 1461-1457

VL - 21

SP - 603

EP - 615

JO - International Journal of Neuropsychopharmacology

JF - International Journal of Neuropsychopharmacology

IS - 6

ER -