Transcriptional Evidence for the Role of Chronic Venlafaxine Treatment in Neurotrophic Signaling and Neuroplasticity Including also Glutatmatergic- and Insulin-Mediated Neuronal Processes

Abstract

ObjectivesVenlafaxine (VLX), a serotonine-noradrenaline reuptake inhibitor, is one of the most commonly used antidepressant drugs in clinical practice for the treatment of major depressive disorder (MDD). Despite being more potent than its predecessors, similarly to them, the therapeutical effect of VLX is visible only 3–4 weeks after the beginning of treatment. Furthermore, recent papers show that antidepressants, including also VLX, enhance the motor recovery after stroke even in non depressed persons. In the present, transcriptomic-based study we looked for changes in gene expressions after a long-term VLX administration.MethodsOsmotic minipumps were implanted subcutaneously into Dark Agouti rats providing a continuous (40 mg/kg/day) VLX delivery for three weeks. Frontal regions of the cerebral cortex were isolated and analyzed using Illumina bead arrays to detect genes showing significant chances in expression. Gene set enrichment analysis was performed to identify specific regulatory networks significantly affected by long term VLX treatment.ResultsChronic VLX administration may have an effect on neurotransmitter release via the regulation of genes involved in vesicular exocytosis and receptor endocytosis (such as Kif proteins, Myo5a, Sv2b, Syn2 or Synj2). Simultaneously, VLX activated the expression of genes involved in neurotrophic signaling (Ntrk2, Ntrk3), glutamatergic transmission (Gria3, Grin2b and Grin2a), neuroplasticity (Camk2g/b, Cd47), synaptogenesis (Epha5a, Gad2) and cognitive processes (Clstn2). Interestingly, VLX increased the expression of genes involved in mitochondrial antioxidant activity (Bcl2 and Prdx1). Additionally, VLX administration also modulated genes related to insulin signaling pathway (Negr1, Ppp3r1, Slc2a4 and Enpp1), a mechanism that has recently been linked to neuroprotection, learning and memory.ConclusionsOur results strongly suggest that chronic VLX treatment improves functional reorganization and brain plasticity by influencing gene expression in regulatory networks of motor cortical areas. These results are consonant with the synaptic (network) hypothesis of depression and antidepressant-induced motor recovery after stroke.

Venlafaxine stimulates PNN proteolysis and MMP‐9‐dependent enhancement of gamma power; relevance to antidepressant efficacy

“…Previously published data have shown that venlafaxine is linked to increased mRNA expression of MMP‐9 in the rat brain (Tamasi et al . ). With respect to the potential to disrupt PV to pyramidal cell input, which would likely have a profound influence on widespread population activity, MMP‐9 has also been shown to diminish PNN integrity (Murase et al .…”

“…Consistent with this possibility is work demonstrating increased MMP‐9 expression in venlafaxine‐treated rats (Tamasi et al . ). While effects of specific monoamines on MMP release from brain‐derived cells have not been extensively studied, in non‐neural cells, norepinephrine has been shown to enhance MMP expression as well as MMP‐dependent endpoints (Yang et al .…”

Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

“…Further, ZDHHC7 palmitoylates sex steroid hormone receptors affecting the rapid intracellular signaling by sex hormones via ERK and AKT kinases [149]; sex steroid hormones are known to modulate synaptic plasticity [150], mood, and antidepressant response [151]. GRIN2B (glutamate receptor ionotropic N-methyl D-aspartate 2) is a known member of the long-term potentiation pathway (as reported above), and the expression of this gene is modulated by venlafaxine together with neurotrophic and neuroplasticity genes [152].…”

Venlafaxine increases cell proliferation and regulates DISC1, PDE4B and NMDA receptor 2B expression in the hippocampus in chronic mild stress mice

“…Studies have shown that venlafaxine prevented chronic stress-induced decreased hippocampal cell proliferation (Feng et al, 2012) and the reduction in NMDA receptor 2B expression (Tamasi et al, 2014;Yilmaz et al, 2011). However, the mechanisms whereby venlafaxine affects DISC1 and its partner PDE4B remain largely unknown.…”