Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants

• Published in: Translational psychiatry Vol. 3; no. 10; p. e313
• Main Authors: Oved, K, Morag, A, Pasmanik-Chor, M, Rehavi, M, Shomron, N, Gurwitz, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.10.2013; Nature Publishing Group
• Subjects: 631/1647/2217/2018; 631/378/2587; 631/92/609; 692/699/476/1414; Behavioral Sciences; Biological Psychology; Cell Adhesion Molecules; Cell Line; Gene Expression Profiling; Humans; Integrin beta3 - drug effects; Integrin beta3 - genetics; Lymphocytes - drug effects; Lymphocytes - metabolism; Medicine; Medicine & Public Health; MicroRNAs - drug effects; MicroRNAs - genetics; Neurogenesis; Neurosciences; Original; original-article; Paroxetine - pharmacology; Pharmacotherapy; Psychiatry; Real-Time Polymerase Chain Reaction; RNA, Messenger - analysis; Sequence Analysis, RNA; Serotonin Plasma Membrane Transport Proteins; Serotonin Uptake Inhibitors - pharmacology; GPIIIa; microRNAs; SSRI antidepressants; human lymphoblastoid cell lines; CD61; serotonin transporter
• DOI: 10.1038/tp.2013.86
• ISSN: 2158-3188

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depression. However, the link between inhibition of serotonin reuptake and remission from depression remains controversial: in spite of the rapid onset of serotonin reuptake inhibition, remission from depression takes several weeks, presumably reflecting synaptogenesis/neurogenesis and neuronal rewiring. We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1 μ M paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes. ITGB3 , coding for integrin beta-3, showed the most consistent altered expression (1.92-fold increase, P =7.5 × 10 −8 ) following chronic paroxetine exposure. Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3 . ITGB3 is crucial for the activity of the serotonin transporter (SERT), the drug target of SSRIs. Moreover, it is presumably required for the neuronal guidance activity of CHL1 , whose expression was formerly identified as a tentative SSRI response biomarker. Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis. Surprisingly, the expression of SERT or serotonin receptors was not modified. Our findings implicate ITGB3 in the mode of action of SSRI antidepressants and provide a novel link between CHL1 and the SERT. Our observations suggest that SSRIs may relieve depression primarily by promoting neuronal synaptogenesis/neurogenesis rather than by modulating serotonin neurotransmission per se .