Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies. In rodent studies, vortioxetine increases glutamate neurotransmission, promotes dendritic branching and spine maturation, and elevates hippocampal expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) at the transcript level. The present study aims to assess the effects of vortioxetine on several neuroplasticity-related molecules in different experimental systems. Chronic (1 month) vortioxetine increased Arc/Arg3.1 protein levels in the cortical synaptosomes of young and middle-aged mice. In young mice, this was accompanied by an increase in actin-depolymerizing factor (ADF)/cofilin serine 3 phosphorylation without altering the total ADF/cofilin protein level, and an increase in the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at serine 845 (S845) without altering serine 831 (S831) GluA1 phosphorylation nor the total GluA1 protein level. Similar effects were detected in cultured rat hippocampal neurons: Acute vortioxetine increased S845 GluA1 phosphorylation without changing S831 GluA1 phosphorylation or the total GluA1 protein level. These changes were accompanied by an increase in α subunit of Ca2+/calmodulin-dependent kinase (CaMKIIα) phosphorylation (at threonine 286) without changing the total CaMKIIα protein level in cultured neurons. In addition, chronic (1 month) vortioxetine, but not fluoxetine, restored the age-associated reduction in Arc/Arg3.1 and c-Fos transcripts in the frontal cortex of middle-aged mice. Taken together, these results demonstrated that vortioxetine modulates molecular targets that are related to neuroplasticity.
AiHYangWYeM. (2011) Differential regulation of AMPA receptor GluA1 phosphorylation at serine 831 and 845 associated with activation of NMDA receptor subpopulations. Neurosci Lett497: 94–98.
2.
AlmeMNWibrandKDagestadG. (2007) Chronic fluoxetine treatment induces brain region-specific upregulation of genes associated with BDNF-induced long-term potentiation. Neural Plast2007: 26496.
3.
AmpueroERubioFJFalconR. (2010) Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience169: 98–108.
BankeTGBowieDLeeH. (2000) Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci20: 89–102.
6.
BaroneEMosserSFraeringPC. (2014) Inactivation of brain Cofilin-1 by age, Alzheimer’s disease and gamma-secretase. Biochim Biophys Acta1842: 2500–2509.
7.
BassaniSFolciAZapataJ. (2013) AMPAR trafficking in synapse maturation and plasticity. Cell Mol Life Sci70: 4411–4430.
8.
BetryCEtievantAPehrsonA. (2015) Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory. Prog Neuropsychopharmacol Biol Psychiatry58: 38–46.
9.
BetryCPehrsonALEtievantA. (2013) The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT(3) receptor antagonism. Int J Neuropsychopharmacol16: 1115–1127.
10.
BramhamCRAlmeMNBittinsM. (2010) The Arc of synaptic memory. Exp Brain Res200: 125–140.
11.
BramhamCRWorleyPFMooreMJ. (2008) The immediate early gene arc/arg3.1: regulation, mechanisms, and function. J Neurosci28: 11760–11767.
12.
ByersCEBarylkoBRossJA. (2015) Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1. Biochim Biophys Acta1850: 1310–1318.
13.
CalabreseBSaffinJMHalpainS. (2014) Activity-dependent dendritic spine shrinkage and growth involve downregulation of cofilin via distinct mechanisms. PLoS One9: e94787.
14.
CarlisleHJManzerraPMarcoraE. (2008) SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. J Neurosci28: 13673–13683.
15.
ChenFDu JardinKGWallerJA. (2016) Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus. Eur Neuropsychopharmacol26: 234–245.
16.
ChenLYRexCSCasaleMS. (2007) Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci27: 5363–5372.
17.
ChenZStockwellJCayabyabFS. (2016) Adenosine A1 receptor-mediated endocytosis of AMPA receptors contributes to impairments in long-term potentiation (LTP) in the middle-aged rat hippocampus. Neurochem Res41: 1085–1097.
18.
ChowdhurySShepherdJDOkunoH. (2006) Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron52: 445–459.
19.
DaleEPehrsonALJeyarajahT. (2016) Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function. CNS Spectr21: 143–161.
20.
DaleEZhangHLeiserSC. (2014) Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus. J Psychopharmacol28: 891–902.
21.
DavisGW (2006) Homeostatic control of neural activity: from phenomenology to molecular design. Annu Rev Neurosci29: 307–323.
22.
DerkachVBarriaASoderlingTR. (1999) Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc Natl Acad Sci USA96: 3269–3274.
23.
DieringGHGustinaASHuganirRL. (2014) PKA-GluA1 coupling via AKAP5 controls AMPA receptor phosphorylation and cell-surface targeting during bidirectional homeostatic plasticity. Neuron84: 790–805.
24.
Du JardinKGLiebenbergNMullerH. (2013) Single dose vortioxetine or ketamine but not fluoxetine increases expression of neuroplasticity related genes in the rat prefrontal cortex. Eur Neuropsychopharmacol23: S392.
25.
EhlersMD (2000) Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron28: 511–525.
FooteMQiaoHGrahamK. (2015) Inhibition of 14–3–3 proteins leads to schizophrenia-related behavioral phenotypes and synaptic defects in mice. Biol Psychiatry78: 386–395.
28.
FukazawaYSaitohYOzawaF. (2003) Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron38: 447–460.
29.
FukunagaK (1993) [The role of Ca2+/calmodulin-dependent protein kinase II in the cellular signal transduction]. Nihon Yakurigaku Zasshi102: 355–369.
GuillouxJPMendez-DavidIPehrsonA. (2013) Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Neuropharmacology73: 147–159.
32.
HayashiYShiSHEstebanJA. (2000) Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science287: 2262–2267.
33.
HayleySLitteljohnD (2013) Neuroplasticity and the next wave of antidepressant strategies. Front Cell Neurosci7: 218.
34.
HeKSongLCummingsLW. (2009) Stabilization of Ca2+-permeable AMPA receptors at perisynaptic sites by GluR1-S845 phosphorylation. Proc Natl Acad Sci USA106: 20033–20038.
35.
HusiHWardMAChoudharyJS. (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci3: 661–669.
36.
KatonaCHansenTOlsenCK (2012) A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol27: 215–223.
37.
KesselsHWMalinowR (2009) Synaptic AMPA receptor plasticity and behavior. Neuron61: 340–350.
38.
LiNLeeBLiuRJ. (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science329: 959–964.
39.
LiYAbdourahmanATammJA. (2015a) Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice. Pharmacol Biochem Behav135: 70–82.
40.
LiYPehrsonALWallerJA. (2015b) A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)’s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression. Front Neurosci9: 279.
41.
LiYRaabyKFSanchezC. (2013) Serotonergic receptor mechanisms underlying antidepressant-like action in the progesterone withdrawal model of hormonally induced depression in rats. Behav Brain Res256: 520–528.
42.
LismanJYasudaRRaghavachariS. (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci13: 169–182.
43.
McIntyreRSLophavenSOlsenCK. (2014) A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol17: 1557–1567.
44.
MahableshwarkarARZajeckaJJacobsonW. (2015) A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology40: 2025–2037.
45.
MenardCGaudreauPQuirionR (2015) Signaling pathways relevant to cognition-enhancing drug targets. Handb Exp Pharmacol228: 59–98.
46.
MessaoudiEKanhemaTSouleJ. (2007) Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci27: 10445–10455.
47.
MoriguchiSShiodaNHanF. (2008) CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region. J Neurochem106: 1092–1103.
48.
MorinJPGuzman-RamosKBermudez-RattoniF (2015) New insights on retrieval-induced and ongoing memory consolidation: Lessons from Arc. Neural Plast2015: 184083.
49.
MorkAPehrsonABrennumLT. (2012) Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther340: 666–675.
50.
NadellaKSSajiMJacobNK. (2009) Regulation of actin function by protein kinase A-mediated phosphorylation of Limk1. EMBO Rep10: 599–605.
51.
NewtonIGForbesMELinvilleMC. (2008) Effects of aging and caloric restriction on dentate gyrus synapses and glutamate receptor subunits. Neurobiol Aging29: 1308–1318.
52.
ObermanLPascual-LeoneA (2013) Changes in plasticity across the lifespan: cause of disease and target for intervention. Prog Brain Res207: 91–120.
RigaMCeladaPSanchezC. (2014) Cortical and hippocampal microcircuits involved in the mechanism of action of the new antidepressant drug vortioxetine. Neurospsychopharmacology39: S632.
55.
RigaMSCeladaPSanchezC. (2013) Role of 5-HT3 receptors in the mechanism of action of the investigational antidepressant vortioxetineEur Neuropsychopharmacol23: S393–394.
56.
RocheKWO’BrienRJMammenAL. (1996) Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron16: 1179–1188.
57.
RomarowskiABattistoneMALa SpinaFA. (2015) PKA-dependent phosphorylation of LIMK1 and Cofilin is essential for mouse sperm acrosomal exocytosis. Dev Biol405: 237–249.
58.
RustMB (2015) ADF/cofilin: a crucial regulator of synapse physiology and behavior. Cell Mol Life Sci72: 3521–3529.
59.
SanchezCAsinKEArtigasF (2015) Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther145: 43–57.
60.
ShonesyBCJalan-SakrikarNCavenerVS. (2014) CaMKII: a molecular substrate for synaptic plasticity and memory. Prog Mol Biol Transl Sci122: 61–87.
61.
SouleJPenkeZKanhemaT. (2008) Object-place recognition learning triggers rapid induction of plasticity-related immediate early genes and synaptic proteins in the rat dentate gyrus. Neural Plast2008: 269097.
62.
SuzukiASternSABozdagiO. (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell144: 810–823.
63.
TanSEWentholdRJSoderlingTR (1994) Phosphorylation of AMPA-type glutamate receptors by calcium/calmodulin-dependent protein kinase II and protein kinase C in cultured hippocampal neurons. J Neurosci14: 1123–1129.
64.
VandesompeleJDe PreterKPattynF. (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol3: RESEARCH0034.
65.
WallerJAChenFSanchezC (2015) Vortioxetine promotes maturation of dendritic spines in vitro: A comparative study in hippocampal cultures. Neuropharmacology103: 143–154.
66.
WangYDongQXuXF. (2013) Phosphorylation of cofilin regulates extinction of conditioned aversive memory via AMPAR trafficking. J Neurosci33: 6423–6433.
67.
YangNHiguchiOOhashiK. (1998) Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature393: 809–812.
68.
ZhaoJWGaoZLJiQY. (2012) Regulation of cofilin activity by CaMKII and calcineurin. Am J Med Sci344: 462–472.
69.
ZhouQHommaKJPooMM (2004) Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron44: 749–757.
70.
ZimmermannAMJeneTWolfM. (2015) Attention-deficit/hyperactivity disorder-like phenotype in a mouse model with impaired actin dynamics. Biol Psychiatry78: 95–106.
