A fundamental step in neuronal development is constituted by the axonal growth and the dendritic branching. Many intra- and extra-cellular signals regulate this process, indeed is very important that the growth of neuronal extremities follow a precise direction in order to reach their target cells.
The distal tip of the axon is a specialized structure called the growth cone. The growth cone interacts with extracellular molecules that operate as repellent or attractant signals. A class of receptors present on axonal and dendritic surface interact with the extracellular signaling molecules, thus triggering cascade pathways that regulate the cytoskeleton structure. Depending on the repellent or attractant properties of extracellular signals, the growth of neuronal tips is either inhibited or promoted. Also, these signals determine the direction of axonal growth, driving growth cones towards the target cells.
A well-known neuronal growth factor, expressed in both adult and developing brain, is the brain-derived neurotrophic factor (BDNF). This molecule, produced by neurons, microglia and astrocytes, plays an important role not only in nervous system development, but also in the neuronal regeneration after a brain injury. The action of BDNF is modulated by adenosine, a widespread nucleoside highly expressed in developing brain. As BDNF, adenosine is released in the extracellular space by neuronal cells, especially astrocytes.
The most known role of adenosine is to interfere with neurotransmitters release at the synaptic level. Recently, however, a new property of adenosine has been investigated: its neurotrophic activity.
BDNF and adenosine interact with membrane receptors TrkB and A2AR, respectively. The activation of A2AR by adenosine has effects on the BDNF pathway, that promotes the dendritic branching. So, there is a synergic interaction between adenosine and BDNF in the neuronal development. On the other hand, adenosine can enhance the axonal growth in a manner independent from BDNF, by activating signaling cascades that directly lead to the modulation of microtubules growth.
The microtubules along the axons form stable structures, but when they reach the growth cones, they spread and act in a dynamic way. They detect the different extracellular conditions, and are able to either grow or shorten, as well as to direct themselves towards a specific direction. The process of microtubule growing or shortening is called dynamic instability, and it is due to the polymerization or depolymerization of their components, a- and b-tubulin.
The labeling of the end-binding protein 3, that accumulates on the growing end of microtubules, has demonstrated that the A2AR activation speeds up the growth of microtubules. At the molecular level, it is believed that the tubulin in dynamic microtubules suffers post-translational modifications that affect its stability. For example, tyrosinated a-tubulin is associated with dynamic microtubules, while acetylated a-tubulin is associated with stable microtubules. The activation of A2AR enhances the tyrosination, thus allowing the growth of microtubules.
Even if most of the mechanisms that underlie the translation of the signals from the extracellular environment to the microtubules are unknown, the role of A2AR may be important as a future target for drug therapies. In fact, some pathologies like depression present a reduced branching of dendrites, due to low levels of the TrkB (the BDNF receptor). So, many antidepressants promote the BDNF expression in order to activate TrkB, that activates the pathways for branching building.
The discovery of the active role of A2AR in the neuronal growth adds a new target for potential antidepressant drugs. A2AR agonists, in fact, can activate BDNF, hence promoting the dendritic growth. This may be a good strategy to alleviate depression symptoms. Moreover, the use of A2AR agonists can help to regenerate neuronal circuits after an atrophy provoked by a brain injury. However, it is also important to notice that A2AR hyper-activation may cause adverse effects in other neurological diseases, like Parkinson’s disease and Huntington’s disease.
The adenosine receptor A2AR has an important role in neuronal growth at the level of the dendritic branching and the axonal growth cone. A2AR activation promotes microtubules dynamic activity either in an independent manner or in synergy with BDNF. A2AR may be a target for antidepressants, but further studies will be needed to better understand the molecular mechanisms that regulate its functionality.
Ribeiro F.F. and Sebastião A.M. Adenosine A2A receptors in neuronal outgrowth: a target for nerve regeneration? Neural Regen Res. 2016 May; 11(5): 706–708.
The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).