Chronic fluoxetine treatment of socially isolated rats modulates prefrontal cortex proteome

Abstract

Exposure to chronic social isolation (CSIS) and dysfunction of serotonin neurotransmission have been implicated in the etiology of major depressive disorder (MDD). Fluoxetine (Flx) has been widely used to treat MDD, however, its molecular mechanisms of action are not yet defined. Hence, we carried out a comparative label-free proteomic approach to identify sub-proteome changes in the prefrontal cortex (PFC) cytosol, non-synaptic mitochondrial (NSM), and synaptosomal-enriched fractions of adult male Wistar rats following chronic social isolation (CSIS) (6 weeks), a rat model of depression, and/or following Flx treatment in CSIS and control rats (15 mg/mL/day) (lasting 3 weeks of 6-weeks CSIS) using liquid chromatography coupled to tandem mass spectrometry. Our aim was to identify the changes in protein levels that enable the identification of (possible) biochemical pathways and processes of importance for the development of depressive-like behavior and the efficacy of Flx treatments. Behavior was assessed with sucrose preference and forced swim tests. In controls, Flx downregulated the proteins involved in endocytosis and vesicle-mediated transport, while predominantly upregulating proteins involved in the microtubule cytoskeleton, intracellular calcium homeostasis, an enzyme linking the glycolytic pathway to the citric acid cycle in NSM, and exocytosis. CSIS affected the PFC proteome by downregulating the proteins involved in proteasome pathway, glutathione antioxidative system, synaptic vesicle cycle, and endocytosis while upregulating the protein levels of enzymes participating in oxidative phosphorylation 1,2. CSIS compromised mitochondrial membrane integrity, as assessed by cytochrome c levels in the cytosol. Effective Flx treatment in CSIS rats resulted in increased synaptic vesicle dynamic, plasticity, and mitochondrial functionality and a suppression of CSIS-induced impairment of these processes 1,2. Our data provide the basis for establishing a marker panel for CSIS-induced depression and effective Flx treatment and highlight the role of NSM and synaptosomal proteins involved in various biochemical pathways as novel investigative protein targets.