Adenosine A2B receptors differently modulate oligodendrogliogenesis and myelination depending on their cellular localization

Abstract Differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs) is a key event for axonal myelination in the brain; this process fails during demyelinating pathologies. Adenosine is emerging as an important player in oligodendrogliogenesis, by activating its metabotropic receptors (A 1 R, A 2A R, A 2B R, and A 3 R). We previously demonstrated that the Gs‐coupled A 2B R reduced differentiation of primary OPC cultures by inhibiting delayed rectifier (I K ) as well as transient (I A ) outward K + currents. To deepen the unclear role of this receptor subtype in neuron‐OL interplay and in myelination process, we tested the effects of different A 2B R ligands in a dorsal root ganglion neuron (DRGN)/OPC cocultures, a corroborated in vitro myelination assay. The A 2B R agonist, BAY60‐6583, significantly reduced myelin basic protein levels but simultaneously increased myelination index in DRGN/OPC cocultures analyzed by confocal microscopy. The last effect was prevented by the selective A 2B R antagonists, PSB‐603 and MRS1706. To clarify this unexpected data, we wondered whether A 2B Rs could play a functional role on DRGNs. We first demonstrated, by immunocytochemistry, that primary DRGN monoculture expressed A 2B Rs. Their selective activation by BAY60‐6583 enhanced DRGN excitability, as demonstrated by increased action potential firing, decreased rheobase and depolarized resting membrane potential and were prevented by PSB‐603. Throughout this A 2B R‐dependent enhancement of neuronal activity, DRGNs could release factors to facilitate myelination processes. Finally, silencing A 2B R in DRGNs alone prevents the increased myelination induced by BAY60‐6583 in cocultures. In conclusion, our data suggest a different role of A 2B R during oligodendrogliogenesis and myelination, depending on their activation on neurons or oligodendroglial cells.