Extracellular vesicles as signals of the hippocampal neurogenic niche: participation in the behavioral effects of cannabinoid and antidepressant drugs

Abstract

Cells are capable of releasing in the extracellular environment various types of endosome-derived membranous extrasynaptic vesicles (LVs) originated from the plasma membrane, called exosomes (EVs, 40-100 nm in diameter) and microvesicles (50-1000nm in diameter), respectively. The EVs are coated with a lipid bilayer and contain proteins, lipids and different types of RNAs provided by the source cell. There transported molecules are biologically active and, when captured by target cells, can regulate gene expression, influence cell proliferation, and modulate angiogenesis and the immune system. They are involved in the transfer of mRNAs, microRNAs (miRNAs), proteins and lipids between cells and are thus capable of modifying the function of receptor cells. The role of exosomes as intercellular messengers has been extensively studied in immune system cells, where they have been shown to modulate antigen presentation and immune response in different cancers. Once secreted, exosomes can interact with target cells to modify their functions, acting as local or paracrine messengers. In addition, they can reach biological fluids such as blood, cerebrospinal fluid, urine etc., and act as remote messengers. Exosomes appear to play a significant role in different stem cell niches, but their functions in neurogenic niches remain poorly understood. This project, therefore, proposes to investigate the nature of the exosome content in the hippocampal neurogenic niche and its role on different niche cell types and the regulation of neurogenesis. Considering that exosomes can reach other biological fluids, we will also investigate if patients diagnosed with major depression or who have experienced traumatic situations have increased number of extracellular vesicles with content similar to those produced in neurogenic niches. The exosomes will be isolated from the conditioned medium of neural stem cells extracted from control or stressed mouse hippocampi or from white blood cells or serum collected from human patients according to the protocol by Cossete et al. (2014). In culture of neural precursors isolated from the dentate gyrus of adult mice or in monocyte culture of patients we will investigate if cannabinoids or antidepressants could alter the content and release of extrasynaptic vesicles, including the cytokines IL1² and IL-6; neurotrophic factors: BDNF, VEGF, NRG1; morphogens: Shh and Wnt3 and cannabinoid receptors CB1 and CB2. We expect to detect the content of exosomes in the hippocampal neurogenic niche and their role on different niche cell types and the regulation of neurogenesis. We also aimed at investigating if antidepressant drugs or interfering with eCB-mediated neurotransmission will alter the content and release of extrasynaptic vesicles and if their content and release will be influenced by prior stress or depression diagnosis. (AU)