Delineation of molecular pathway activities of the chronic antidepressant treatment response suggests important roles for glutamatergic and ubiquitin–proteasome systems

Abstract

The aim of this study was to identify molecular pathways related to antidepressant response. We administered paroxetine to the DBA/2J mice for 28 days. Following the treatment, the mice were grouped into responders or non-responders depending on the time they spent immobile in the forced swim test. Hippocampal metabolomics and proteomics analyses revealed that chronic paroxetine treatment affects glutamate-related metabolite and protein levels differentially in the two groups. We found significant differences in the expression of N-methyl-d-aspartate receptor and neuronal nitric oxide synthase proteins between the two groups, without any significant alterations in the respective transcript levels. In addition, we found that chronic paroxetine treatment altered the levels of proteins associated with the ubiquitin–proteasome system (UPS). The soluble guanylate cyclase-β1, proteasome subunit α type-2 and ubiquitination levels were also affected in peripheral blood mononuclear cells from antidepressant responder and non-responder patients suffering from major depressive disorder. We submit that the glutamatergic system and UPS have a crucial role in the antidepressant treatment response in both mice and humans.

Translational Identification of Transcriptional Signatures of Major Depression and Antidepressant Response

“…It has also been observed from work on postmortem brains of individuals with major psychiatric disorders that protein synthesis, essentially through dysregulation of ribosomal genes and messenger RNA processing, was a pathway of central importance to psychiatric health (Darby et al, 2016 ). Our own results are convergent with these findings, with the addition of ubiquitin-mediated proteolysis (Figures 3C , 5C ), that has also been previously regarded as crucial in the antidepressant treatment response in both mice and humans (Park et al, 2017 ). Thus, our candidate gene list contained two players involved in the translational machinery: the immunoglobulin mu-binding protein 2 ( IGHMBP2 ), encoding a DNA/RNA helicase (De Planell-Saguer et al, 2009 ), and RPL35A , encoding a component of the large subunit of the ribosome.…”

Translational identification of transcriptional signatures of major depression and antidepressant response

“…It has also been observed from work on postmortem brains of individuals with major psychiatric disorders that protein synthesis, essentially through dysregulation of ribosomal genes and messenger RNA processing, was a pathway of central importance to psychiatric health (Darby et al, 2016). Our own results are convergent with these findings, with the addition of ubiquitin-mediated proteolysis (Figures 3C, 5C), that has also been previously regarded as crucial in the antidepressant treatment response in both mice and humans (Park et al, 2017). Thus, our candidate gene list contained two players involved in the translational machinery: the immunoglobulin mu-binding protein 2 (IGHMBP2), encoding a DNA/RNA helicase (De Planell-Saguer et al, 2009), and RPL35A, encoding a component of the large subunit of the ribosome.…”

Blood plasma/IgG N-glycome biosignatures associated with major depressive disorder symptom severity and the antidepressant response

“…Due to the small number of patient specimens and the fact that patients received different antidepressant medications our study suffers from low statistical power. However, since our previous studies with the same patient cohorts showed consistent molecular pathway differences between responders and non-responders 25 , 26 , pharmacological heterogeneity in our cohorts may not be critical. We also found little overlap between age-related and treatment response-related N-glycans/traits.…”

“…Proteomics has been widely used to identify affected proteins and pathways in major depressive disorders (MDD), which has provided insights into molecular mechanisms of MDD and its treatment. Energy metabolism and synaptic pathways have repeatedly been associated with MDD 21 – 24 and based on our recent studies also with the antidepressant treatment response 25 – 27 .…”