ADENOSINE A2A RECEPTOR MODULATION OF NEURONAL MATURATION

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Unveiling the trophic actions of adenosine A2A receptors in neurite outgrowth and postnatal neurogenesis : interaction with brain-derived neurotrophic factor

Publication . Ribeiro, Ana Filipa Ferreira da Cunha, 1987-; Sebastião, Ana Maria, 1958-

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.

2017Doctoral thesis

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Adenosine A2A receptors in neuronal outgrowth: a target for nerve regeneration?

Publication . Sebastião, Ana M; Ribeiro, Filipa

Axonal and dendritic outgrowth are fundamental processes in the development of the nervous system. During this period, neurons change their morphology from a simple bipolar shape into a mature complex shape. Neurons develop dendrites and extend long or short axons that travel through a complex path until reaching target cells and form functional and accurate neuronal circuits.

2016Journal article

Open access

Interaction between cannabinoid type 1 and type 2 receptors in the modulation of subventricular zone and dentate Gyrus neurogenesis

Publication . Rodrigues, Rui S.; Ribeiro, Filipa; Ferreira, Filipa; Vaz, Sandra H.; Sebastião, Ana M; Xapelli, Sara

Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG). Cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CB1R and CB2R in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation). We focused on a putative crosstalk between CB1R and CB2R to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3) Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining), an effect blocked by either CB1R or CB2R selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CB1R and CB2R. Cell proliferation in the SVZ was not affected by the non-selective receptor agonist, but it was enhanced by CB1R selective activation. However, either CB1R or CB2R selective antagonists abolished the effect of the CB1R agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging) was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CB1R or CB2R selective agonists and blocked by either CB1R or CB2R selective antagonists, cross-antagonism being evident. In summary, our findings indicate a tight interaction between CB1R and CB2R to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain.

2017Journal article

Open access

Cannabinoid actions on neural stem cells: implications for pathophysiology

Publication . Rodrigues, Rui S.; Lourenço, Diogo M.; Paulo, Sara L; Mateus, Joana; Ferreira, Miguel F.; Mouro, Francisco; Moreira, João B.; Ribeiro, Filipa; Sebastião, Ana M; Xapelli, Sara

With the increase of life expectancy, neurodegenerative disorders are becoming not only a health but also a social burden worldwide. However, due to the multitude of pathophysiological disease states, current treatments fail to meet the desired outcomes. Therefore, there is a need for new therapeutic strategies focusing on more integrated, personalized and effective approaches. The prospect of using neural stem cells (NSC) as regenerative therapies is very promising, however several issues still need to be addressed. In particular, the potential actions of pharmacological agents used to modulate NSC activity are highly relevant. With the ongoing discussion of cannabinoid usage for medical purposes and reports drawing attention to the effects of cannabinoids on NSC regulation, there is an enormous, and yet, uncovered potential for cannabinoids as treatment options for several neurological disorders, specifically when combined with stem cell therapy. In this manuscript, we review in detail how cannabinoids act as potent regulators of NSC biology and their potential to modulate several neurogenic features in the context of pathophysiology.

2019-04-05Journal article

Open access

Purine nucleosides in neuroregeneration and neuroprotection

Publication . Ribeiro, Filipa; Xapelli, Sara; Miranda-Lourenço, Catarina; Tanqueiro, Sara; Fonseca-Gomes, João; Diógenes, Maria José; Ribeiro, Joaquim A.; Sebastião, Ana M

In the present review, we stress the importance of the purine nucleosides, adenosine and guanosine, in protecting the nervous system, both centrally and peripherally, via activation of their receptors and intracellular signalling mechanisms. A most novel part of the review focus on the mechanisms of neuronal regeneration that are targeted by nucleosides, including a recently identified action of adenosine on axonal growth and microtubule dynamics. Discussion on the role of the purine nucleosides transversally with the most established neurotrophic factors, e.g. brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), is also focused considering the intimate relationship between some adenosine receptors, as is the case of the A2A receptors, and receptors for neurotrophins. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.

2016Journal article

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