Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

Abstract

Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.

Sgk1 regulates desmoglein 1 expression levels in oligodendrocytes in the mouse corpus callosum after chronic stress exposure

“…It is well known that Rho GTPase signaling and calcium are important cell adhesion regulators in the brain [27e29]. Furthermore, a recent study has indicated that Rho GTPase-related pathways in oligodendrocytes and neurons are involved in antidepressant effects in the hippocampus [30]. Our study suggests that Dsg1 upregulation in oligodendrocytes may be associated with the pathogenesis of major depression following exposure to chronic stress, and implicates morphological regulation of oligodendrocytes by Dsg1-Rho GTPase cascades as a possible mechanism.…”

Regulation of alternative gene transcription in the striatum in response to antidepressant drugs

“…The binding properties of factors from the four major classes of transcriptional regulators are presented in Figure S5. Piechota et al, 2014 13 by dexamethasone exhibited nonspecific isoform regulation (difference in proportion, P = 9.49 x 10 -8 ;…”

“…A C C E P T E D ACCEPTED MANUSCRIPT Piechota et al, 2014 2 M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Piechota et al, 2014 …”

“…Nevertheless, the genetic elements and pathways that control the selection of an active transcription initiation or termination are not entirely understood (Davuluri et al, 2008). Multiple studies have attempted to profile the effects of antidepressants using highthroughput gene expression arrays (Bohm et al, 2006;Conti et al, 2007;Korostynski et al, 2013;Landgrebe et al, 2002;Malki et al, 2012;Patricio et al, 2014). However, the previous findings were not entirely conclusive, and more complementary knowledge of antidepressant-regulated genes in the brain is required.…”

“…A C C E P T E D ACCEPTED MANUSCRIPT Piechota et al, 2014 8 data are discretely distributed, they approximately follow normal distribution and hence, statistical significance was analyzed using parametric statistics (Rapaport et al, 2013). One-way ANOVA was used for in vivo antidepressant treatment and t-tests were used for ex vivo cellular experiments.…”