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Adenosine is emerging as an important player in oligodendrogliogenesis, by activating its metabotropic receptors (A<jats:sub>1<\/jats:sub>R, A<jats:sub>2A<\/jats:sub>R, A<jats:sub>2B<\/jats:sub>R, and A<jats:sub>3<\/jats:sub>R). We previously demonstrated that the Gs\u2010coupled A<jats:sub>2B<\/jats:sub>R reduced differentiation of primary OPC cultures by inhibiting delayed rectifier (I<jats:sub>K<\/jats:sub>) as well as transient (I<jats:sub>A<\/jats:sub>) outward K<jats:sup>+<\/jats:sup> currents. To deepen the unclear role of this receptor subtype in neuron\u2010OL interplay and in myelination process, we tested the effects of different A<jats:sub>2B<\/jats:sub>R ligands in a dorsal root ganglion neuron (DRGN)\/OPC cocultures, a corroborated in vitro myelination assay. The A<jats:sub>2B<\/jats:sub>R agonist, BAY60\u20106583, 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<jats:sub>2B<\/jats:sub>R antagonists, PSB\u2010603 and MRS1706. To clarify this unexpected data, we wondered whether A<jats:sub>2B<\/jats:sub>Rs could play a functional role on DRGNs. We first demonstrated, by immunocytochemistry, that primary DRGN monoculture expressed A<jats:sub>2B<\/jats:sub>Rs. Their selective activation by BAY60\u20106583 enhanced DRGN excitability, as demonstrated by increased action potential firing, decreased rheobase and depolarized resting membrane potential and were prevented by PSB\u2010603. Throughout this A<jats:sub>2B<\/jats:sub>R\u2010dependent enhancement of neuronal activity, DRGNs could release factors to facilitate myelination processes. Finally, silencing A<jats:sub>2B<\/jats:sub>R in DRGNs alone prevents the increased myelination induced by BAY60\u20106583 in cocultures. In conclusion, our data suggest a different role of A<jats:sub>2B<\/jats:sub>R during oligodendrogliogenesis and myelination, depending on their activation on neurons or oligodendroglial cells.<\/jats:p>","DOI":"10.1002\/glia.24593","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T09:25:13Z","timestamp":1722331513000},"page":"1985-2000","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Adenosine <scp>A<sub>2B<\/sub><\/scp> receptors differently modulate oligodendrogliogenesis and myelination depending on their cellular localization"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-456X","authenticated-orcid":false,"given":"Federica","family":"Cherchi","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA) University of Florence  Florence 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