Activation of signaling pathways downstream of the brain-derived neurotrophic factor receptor, TrkB, in the rat brain by vagal nerve stimulation and antidepressant drugs

Abstract

Vagal nerve stimulation (VNS) has been approved for treatment resistant depression (TRD) by the Food and Drug Administration (FDA) since 2005. However, the cellular and molecular targets responsible for its effects are still not characterized. Previously, chronic administration of VNS to rats was found to phosphorylate tyrosine 515 on TrkB, the neurotrophin receptor, whereas traditional antidepressants did not do this. In the present study, Western blot analysis was used to characterize activation due to phosphorylation in the hippocampus of down-stream pathways linked to specific key tyrosine residues on TrkB (namely Y816 and Y515) after either acute or chronic administration of VNS and traditional antidepressant drugs. Chronic administration of VNS caused phosphorylation of effectors linked to Y 515; namely Akt, ERK and p70S6 kinase, but this was not produced by either desipramine or sertraline. All the treatments, when given chronically, caused phosphorylation of the transcription factor, CREB. Acute administration of all the treatments also caused phosphorylation of PLCγ1 but this was not maintained with chronic treatment. Further research is required to determine what role, if any, activation of down-stream targets of Y515 plays in the behavioural effects of VNS.

Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: Comparison with desipramine

“…As discussed (Shah et al, 2014), both VNS and ketamine modulate signaling pathways downstream of TrkB, such as the mammalian target of rapamycin (mTOR) pathway within the hippocampus indicated by increased phosphorylation of p70S6 kinase, in addition to AKT and ERK (Autry et al, 2011, Duman and Aghajanian, 2012, Carreno and Frazer, 2014). More importantly, these effects are not seen with chronic administration of traditional antidepressants (Carreno and Frazer, 2014). …”

“…After rapid decapitation, brains were removed and the left hippocampus dissected out. Sample preparation for Western blotting, blotting procedure, visualization and quantification of blots was carried out as described by Carreno et al (2014). Samples were homogenized in lysis buffer (50mM Tris, 1 mM EDTA, 0.35% Sodium deoxycholate, 150 mM NaCl, 1% Igepal, 10% glycerol, 0.1% SDS with pH adjusted to 7.4 and supplemented with a cocktail of protease and phosphatase inhibitors), incubated on ice for 30 min and centrifuged (16,000 g for 20 min).…”

“…However, only acute or chronic VNS causes phosphorylation at Y515, linked to Ras/MAPK and PI3K pathways (Furmaga et al, 2012, Carreno and Frazer, 2014). It is currently not certain if AD-induced TrkB activation is due to BDNF release, or to a different neurotrophin or is independent of neurotrophins (Rantamaki and Castren, 2008).…”

ERK1/2 phosphorylation is involved in the antidepressant-like action of 2,5-diphenyl-3-(4-fluorophenylseleno)-selenophene in mice

“…It is now well established that antidepressants affect different signalling pathways like that producing phosphorylation of CREB (Alboni et al, 2010;Blendy, 2006;Carreno and Frazer, 2014;First et al, 2013;Kuo et al, 2013;Reus et al, 2011). Previous researches indicated that the ERK-CREB signal system may be involved in the molecular mechanism of depression (Qi et al, 2006) and some antidepressant therapies increase both phosphorylated ERK and CREB levels in brain of rodents after repeated treatment (Carreno and Frazer, 2014;Musazzi et al, 2010;Qi et al, 2008;Tardito et al, 2009). Wherever, while early peak of ERK activation is commonly observed, CREB phosphorylation is generally seen only after days or weeks after antidepressant treatment (Di Benedetto et al, 2012).…”

“…Although most studies focus on serotonergic and noradrenergic systems (Millan, 2004), recent evidences have identified modifications of intracellular signalling proteins and target genes that could contribute to the pharmacological action of antidepressant therapy (Blendy, 2006;Carreno and Frazer, 2014;Kuo et al, 2013;models results in antidepressant-like behaviors (Blendy, 2006;Carreno and Frazer, 2014;Reus et al, 2011). Phosphorylation, and therefore activation of CREB can be induced by a number of upstream signalling cascades, including MAPK/ERK (Blendy, 2006).…”