BDNF and adenosine A_2A receptor interaction regulates oligodendrogenesis from postnatal neural stem cells

Oligodendrocytes (OLs) are vital for myelin formation in the Central Nervous System, and their differentiation from precursor cells is critical for remyelination in demyelinating disorders. These cells originate either from the maturation of oligodendrocyte precursor cells (OPCs), present throughout the brain parenchyma, or from the differentiation of neural stem cells located in the subventricular zone (SVZ-NSCs). However, the molecular signals regulating their differentiation remain partially understood. In this work, we studied the role of brain-derived neurotrophic factor (BDNF) and adenosine A_2A receptor, as well as their potential interaction, in modulating oligodendrogenesis using postnatal SVZ-derived neurosphere cultures. In these cultures, BDNF tended to increase mRNA expression levels of OPC markers after 2 days in vitro (DIV), an effect blocked by the A_2A receptor antagonist ZM 241385. This early transcriptional regulation by BDNF was followed by changes in the percentage of both OPCs and mature OLs in culture at DIV 7 and 14. Interestingly, A_2A receptor blockade prevented the BDNF-induced increase in OL differentiation at DIV 14. Concerning the morphology of mature OLs, BDNF transiently reduced proximal branching at DIV 7, an effect absent at 14 DIV, when all treatments displayed similar morphologies. At the protein level, BDNF enhanced TrkB expression at DIV 14 in an A_2A receptor-dependent manner, without altering A_2A receptor expression itself, further supporting a modulatory role of A_2A receptors in BDNF receptor signalling. Overall, our results identify BDNF as a key regulator of OL differentiation and reveal an A_2A receptor-BDNF interaction modulating this differentiation process.