Dataset Information

Fluoxetine stimulates synaptic vesicular dynamic and mitochondrial energy metabolism in prefrontal cortex of socially isolated rats

ABSTRACT: Identifying adequate biomarkers of major depressive disorder (MDD) and therapy has been the goal of many studies. Many molecular alterations associated with the pathophysiology of MDD reside within the synapse. Fluoxetine (Flx) is the most commonly prescribed antidepressant, but the mechanism of its action is unclear. Hence, we performed a comparative proteomics of synaptosomal-enriched fractions from prefrontal cortex of adult male Wistar rats exposed to CSIS (6 weeks) and after chronic Flx treatment of controls (3 weeks) and CSIS-exposed rats (lasting 3 weeks of 6-week-CSIS). Our aim was to profile synaptosomal proteome changes representative of possible time-consuming events underlying the CSIS-induced depressive-like behavior and antidepressant property of Flx. Bioinformatic data of Flx-treated control rats revealed down-expression of proteins that mainly participate in proteasome system and vesicle mediated transport as well as predominantly increases expression of exocytosis-associated proteins. CSIS led to decreased expression of proteins involved in ATP metabolic process, synaptic vesicle endocytosis and proteasome system, while increased energy yielding glycolytic pathway. Flx treatment of CSIS rats predominantly increases expression of exo/endocytosis-associated proteins and Cox5a, mitochondria-associated proteins involved in oxidative phosphorylation. Overall, synaptoproteomic profiling indicated that Flx stimulated synaptic vesicular dynamics by enhancing endo/exocytosis and mitochondrial energy metabolism in CSIS rats that might be critical targets for pharmacological treatments for MDD.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Dragana Filipovic

LAB HEAD: Dragana Filipović

PROVIDER: PXD029575 | Pride | 2023-11-10

REPOSITORIES: Pride

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Publications

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

Dataset Information

Fluoxetine stimulates synaptic vesicular dynamic and mitochondrial energy metabolism in prefrontal cortex of socially isolated rats

Publications

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

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