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

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.