Interplay between serotonin 5-HT1A and 5-HT7 receptors in stress-related disorders : PhD thesis

Antoniuk, Svitlana

Skip to main menu
Skip to search engine
Skip to content
Skip to footer

Interplay between serotonin 5-HT1A and 5-HT7 receptors in stress-related disorders : PhD thesis

Download

Description
Information

Title: Interplay between serotonin 5-HT1A and 5-HT7 receptors in stress-related disorders : PhD thesis

Abstract:

Stress-related disorders are highly prevalent diseases all over the world. Accumulating data indicate that the serotonergic system is strongly linked with the pathogenesis of depression. Numerous studies based on molecular biology, genetic, histological, and behavioral approaches have shown that serotonin receptors, in particular 5-HT1A and 5-HT7, might mediate the stress response in both rodents and humans. However, mechanisms explaining an involvement of 5-HT1A and 5-HT7 receptors in stress-related diseases are not completely understood. Previous studies of our research group have shown that 5-HT1A and 5-HT7 receptors form heterodimers in the recombinant system, in neuronal cultures and in the mouse brain, which in turn leads to changes in the receptor-mediated signaling. In this regard, the aim of this project was to investigate functional implication of 5-HT1AR/5-HT7R heterodimerization by modeling depression in animals.First, a theoretical study based on meta-analysis was performed to verify the applicability of the chronic unpredictable stress protocol for modeling depression in different strains of rodents. Using this approach, we have demonstrated that both rats and mice showed anhedonic behavior after implementation of the chronic unpredictable stress protocol. In this study, C57BL/6J mice were chosen as the best model due to their higher susceptibility to stress protocol upon shorter stress duration in comparison to other rodent strains, availability of transgenic lines bred on C57BL/6J genetic background, and lower cost of depression modeling compared to rats. The depressive phenotype was assessed based on anhedonic and despair parameters as well as body weight fluctuation. Second, the investigation of 5-HT1A and 5-HT7 receptors expression profiles in different mouse brain regions during postnatal development was performed. Thus, our data have shown that the 5-HT1AR protein level was upregulated in the prefrontal cortex and hippocampus compared to the raphe nuclei, whereas the level of the 5-HT7R did not differ. Additionally, applying qRT-PCR it has been demonstrated that the 5-HT1ARs mRNA is the dominant subpopulation in comparison to the 5-HT7Rs mRNA in the prefrontal cortex and hippocampus during brain development. Third, the interaction between 5-HT1A and 5-HT7 receptors using depression-like model in C57BL/6J mice was investigated. Noteworthy, the most prominent changes in heterodimerization profile of 5-HT1A and 5-HT7 receptors were observed in the medial prefrontal cortex and hippocampal dentate gyrus of C57BL/6J mice. We have obtained a decrease in the number of 5-HT1AR/5-HT7R heterodimeric complexes in the stressed anhedonic mice in comparison to stressed control and stressed resilient animals. In contrast, no significant changes in the 5-HT1AR and 5-HT7R heterodimerization profile were detected in the dorsal raphe nuclei. In conclusion, our data revealed that the chronic unpredictable stress paradigm represents a robust and reproducible model for the depression-like behavior in rodents. Moreover, the number of 5-HT1AR/5-HT7R heterodimers was decreased in the prefrontal cortex of C57BL/6J mice upon chronic unpredictable stress, suggesting functional role of 5-HT1AR and 5-HT7R interaction in development of depressive-like behavior.