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Publication
Unveiling the trophic actions of adenosine A2A receptors in neurite outgrowth and postnatal neurogenesis : interaction with brain-derived neurotrophic factor
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Advisor(s)
Abstract(s)
In the postnatal mammalian brain, neurogenesis occurs constitutively in two main regions: in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). These neurogenic niches are postnatal sources of new neurons that functionally integrate into the existing circuitry. SVZ future neurons migrate long distances through the rostral migratory stream (RMS) towards the olfactory bulb (OB), whilst SGZ future neurons migrate short distances to the granule cell layer of the DG. Displaying a simple bipolar shape when reaching their final placement, new neurons start to acquire a more complex morphology. They extend and branch their axonal and dendritic processes towards specific target cells with which they establish functional neuronal networks. All the events of progenitor cell proliferation and differentiation into neurons, as well as of neuronal migration, development and integration, are tightly regulated by several factors present in the surrounding extracellular environment. However, there is still a lack of knowledge about the factors and correspondent mechanisms that regulate neurogenesis and neuronal morphology. Among these factors are brain-derived neurotrophic factor (BDNF) and adenosine. BDNF has been associated to the regulation of adult neurogenesis both from SGZ and SVZ. Additionally, BDNF trophic actions are extended to the dendritic and axonal morphologies. On the other hand, adenosine, which is a known modulator of synaptic transmission, including of BDNF synaptic actions, has been much less investigated in terms of its influence over neurogenesis and neurite outgrowth. This work aimed to evaluate and characterize the trophic actions of A2ARs in SGZ and SVZ neurogenesis and their role on axonal an dendritic growth during neurite development. Furthermore, the impact of A2ARs on BDNF actions during these processes was also studied. We show for the first time that A2AR endogenous activation is essential for BDNF-mediated increase in cell proliferation and in the formation of new neurons in both neurogenic niches. Moreover, A2AR exogenous activation interferes in specific and distinct time windows of SGZ and SVZ neurogenesis, displaying different roles in these neurogenic niches. While A2AR activation enhanced neural stem cell self-renewal and promoted an increase in the number of neurons in DG-derived cultures, without affecting cell proliferation as a whole, in SVZ-derived cultures, there was no effect of A2AR activation upon these processes. These results were, indeed, confirmed by the activation of this adenosine receptor in an in vivo rat model. Here, A2AR activation promoted and increase in the number of newborn neurons in the DG, but not in the OB, without affecting cell proliferation in both SGZ and SVZ neurogenic areas. In what concerns morphogenesis, it was the opposite, while neurite outgrowth of DG-derive cultured neurons was not affected by A2AR agonist, in SVZ-derived neurons both axonal and dendritic length and branching were enhanced. In primary cortical neuronal cultures, we detected that selective activation of A2AR enhances axonal elongation and dendritic branching. The action of A2ARs upon dendritic branching was shown to be dependent on the presence of endogenous BDNF, whereas the influence of A2ARs upon axonal elongation was independent of endogenous BDNF. Moreover, A2ARmediated axonal elongation was also dependent on phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and phospholipase C (PLC) pathways, while dendritic branching was dependent on protein kinase A (PKA). In consonance with the action over axonal elongation, A2AR activation promoted a decrease in microtubule stability and an increase in microtubule growth speed in axonal growth cones. The data herein described reveal a novel role for A2ARs as modulators of neuronal differentiation in the DG and modulators of axonal and dendritic growth in cortical-derived neurons. These results also contribute to a better understanding of the process of neurogenesis in SVZ and DG and provide new insights for A2ARs regulation of neuronal development and axonal regeneration.
Description
Tese de doutoramento, Ciências Biomédicas (Neirociências), Universidade de Lisboa, Faculdade de Medicina, 2017
Keywords
Receptor A2A de adenosina Fator neurotrófico derivado do cérebro (BDNF) Neurogénese Crescimento neuronal Giro denteado Ventrículos laterais Teses de doutoramento - 2017