Analysis of region-specific changes in gene expression upon treatment with citalopram and desipramine reveals temporal dynamics in response to antidepressant drugs at the transcriptome level.

Magdalena Gąska,Marta Dziedzicka-Wasylewska,Joanna Solich,Małgorzata J Krawczyk,Maciej Kuśmider,Agata Faron-Górecka,Krzysztof Kułakowski

doi:10.1007/s00213-012-2714-0

Abstract

RationaleThe notion that the onset of action of antidepressant drugs (ADs) takes weeks is widely accepted; however, the sequence of events necessary for therapeutic effects still remains obscure.ObjectiveWe aimed to evaluate a time-course of ADs-induced alterations in the expression of 95 selected genes in 4 regions of the rat brain: the prefrontal and cingulate cortices, the dentate gyrus of the hippocampus, and the amygdala.MethodsWe employed RT-PCR array to evaluate changes during a time-course (1, 3, 7, 14, and 21 days) of treatments with desipramine (DMI) and citalopram (CIT). In addition to repeated treatment, we also conducted acute treatment (a single dose of drug followed by the same time intervals as the repeated doses).ResultsTime-dependent and structure-specific changes in gene expression patterns allowed us to identify spatiotemporal differences in the molecular action of two ADs. Singular value decomposition analysis revealed differences in the global gene expression profiles between treatment types. The numbers of characteristic modes were generally smaller after CIT treatment than after DMI treatment. Analysis of the dynamics of gene expression revealed that the most significant changes concerned immediate early genes, whose expression was also visualized by in situ hybridization. Transcription factor binding site analysis revealed an over-representation of serum response factor binding sites in the promoters of genes that changed upon treatment with both ADs.ConclusionsThe observed gene expression patterns were highly dynamic, with oscillations and peaks at various time points of treatment. Our study also revealed novel potential targets of antidepressant action, i.e., Dbp and Id1 genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-012-2714-0) contains supplementary material, which is available to authorized users.

Highlights

Despite the increasing prescription of antidepressant drugs (ADs) and their intensive investigation for almost five decades, the mechanisms of their antidepressant action remain unresolved
We show that highly complex sets of gene expression profiles can be represented by a small number of “characteristic modes” that capture most of the expression information in the temporal patterns of gene expression change
No modes could be generated for the prefrontal cortex (PCX) after repeated CIT treatment and for the AMY after repeated and single-dose CIT treatment because the number of genes selected in analysis of variance (ANOVA) for a specific treatment type was smaller than the number of the time points

Summary

Introduction

Despite the increasing prescription of antidepressant drugs (ADs) and their intensive investigation for almost five decades, the mechanisms of their antidepressant action remain unresolved. Based on the above-mentioned data and literature survey (Boehm et al 2006; Carr et al 2010; Drigues et al 2003; Frechilla et al 1998; Orsetti et al 2008; Urani et al 2005), genes of interest that are believed to be crucial in ADs action were selected for our study These genes encode receptors (e.g., Adra, Adrb, Cnr, Drd, GalR, Gria, and Opr), transcription factors (e.g., Creb, Crem, Egr, Fos, Jun, Jund, and Sp1), genes involved in inflammatory responses (e.g., Il10r, Il1r, Il6r, Stat, and Tnf), HPA activity (e.g., Crhbp, Crhr, and Ucn), neuronal apoptosis and synaptic plasticity (e.g., Bcl[2], Bdnf, Cacna, Cdk, Ntf, and Vgf), and a number of other genes previously unlinked directly to ADs action but important because of their involvement in the transcriptional machinery of the cell (e.g., Aes, Arnt, Cebpb, Dbp, Esr[2], Ets, Gata[2], Hdac, Id1, Nr, Pax[6], and Yy1). In contrast to the vast majority of preclinical studies, which have been conducted using animals treated with ADs repeatedly (typically 7–14 days), we decided to conduct a temporal analysis of the expression of genes regulated by ADs in specific brain regions

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Conclusion