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Chronic fluoxetine treatment of socially isolated rats modulates prefrontal cortex proteome

ABSTRACT: Chronic social isolation (CSIS) is a risk factor for human major depressive disorder (MDD). Fluoxetine (Flx) is an antidepressant commonly used for first-line MDD therapy. However, its downstream mechanisms of action, beyond serotonergic signaling, remain elusive. We aimed to analyze the effects of CSIS followed by chronic Flx treatment on proteome changes in the adult male rat prefrontal cortex (PFC) cytosolic and non-synaptic mitochondria (NSM)-enriched fractions. Treatment with Flx ameliorated depression-like behaviors in CSIS-induced rat model of depression as assessed by sucrose preference test and forced swim test. Proteomic data showed that Flx increased the expression of proteins involved in cytoskeleton and regulation of intracellular Ca2+ homeostasis in the cytosol and of enzymes linking the glycolytic pathway to the citric acid cycle (Dlat) and ATPase-coupled ion transmembrane transport in NSM. CSIS resulted in down-regulation of cytosolic proteins involved in proteasome/ubiquitination processes and glutathione antioxidative system and up-regulated expression of key enzymes participating in oxidative phosphorylation. Presence of cytochrome c in the cytosol indicated compromised mitochondrial membrane integrity. Flx treatment in CSIS rats showed predominately an upregulation of vesicle-mediated transport proteins and reduced Uqcrfs1 along with transport in NSM, favoring reduced energy metabolism. Our data suggest that proteins from both cytosol and NSM-enriched fractions are affected by Flx in a key brain region associated with stress response, cognitive process and regulation of emotion.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Dragana Filipovic

LAB HEAD: Dragana Filipovića

PROVIDER: PXD026202 | Pride | 2023-11-10

REPOSITORIES: Pride

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Chronic Fluoxetine Treatment of Socially Isolated Rats Modulates Prefrontal Cortex Proteome.

Filipović Dragana D Novak Božidar B Xiao Jinqiu J Yan Yu Y Yeoh Karin K Turck Christoph W CW

Neuroscience 20220810

Fluoxetine (Flx) is the most commonly used antidepressant to treat major depressive disorder. However, its molecular mechanisms of action are not defined as yet. A comparative proteomic approach was used to identify proteome changes in the prefrontal cortex (PFC) cytosolic and non-synaptic mitochondria (NSM)-enriched fractions of adult male Wistar rats following chronic social isolation (CSIS), a rat model of depression, and Flx treatment in CSIS and control rats, using liquid chromatography onl ...[more]

PMID: 35963583

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Project description:Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e. fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ~50–63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-days chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n=18), or Flx non-responder mice (Flx-NR, n=7). Then, Flx-NR mice received 7 sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down- and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology. remark for sample name : ECTR=Flx-NR-ES, C=cort/Veh, CFNR= Flx-NR

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