title: Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.
abstract: 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 μM 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.
authors.affiliation: 1] Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel [2] Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: K
authors.initials: K
authors.lastname: Oved
authors.forename: A
authors.initials: A
authors.lastname: Morag
authors.forename: M
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.forename: M
authors.initials: M
authors.lastname: Rehavi
authors.forename: N
authors.initials: N
authors.lastname: Shomron
authors.forename: D
authors.initials: D
authors.lastname: Gurwitz
mesh_terms: D015815:Cell Adhesion Molecules; D002460:Cell Line; D020869:Gene Expression Profiling; D006801:Humans; D039661:Integrin beta3 / Q000187:drug effects* / Q000235:genetics; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D035683:MicroRNAs / Q000187:drug effects* / Q000235:genetics; D055495:Neurogenesis; D017374:Paroxetine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis*; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D015815:Cell Adhesion Molecules; D039661:Integrin beta3; D035683:MicroRNAs; D017374:Paroxetine; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C490650:CHL1 protein, human; C061248:ITGB3 protein, human; C525709:MIR221, human; C525710:MIR222, human; C493230:SLC6A4 protein, human