title: Axonal elongation and dendritic branching is enhanced by adenosine A2A receptors activation in cerebral cortical neurons.
abstract: Axon growth and dendrite development are key processes for the establishment of a functional neuronal network. Adenosine, which is released by neurons and glia, is a known modulator of synaptic transmission but its influence over neuronal growth has been much less investigated. We now explored the action of adenosine A2A receptors (A2AR) upon neurite outgrowth, discriminating actions over the axon or dendrites, and the mechanisms involved. Morphometric analysis of primary cultures of cortical neurons from E18 Sprague-Dawley rats demonstrated that an A2AR agonist, CGS 21680, enhances axonal elongation and dendritic branching, being the former prevented by inhibitors of phosphoinositide 3-kinase, mitogen-activated protein kinase and phospholipase C, but not of protein kinase A. By testing the influence of a scavenger of BDNF (brain-derived neurotrophic factor) over the action of the A2AR agonist and the action of a selective A2AR antagonist over the action of BDNF, we could conclude that while the action of A2ARs upon dendritic branching is dependent on the presence of endogenous BDNF, the influence of A2ARs upon axonal elongation is independent of endogenous BDNF. 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. In conclusion, we disclose a facilitatory action of A2ARs upon axonal elongation and microtubule dynamics, providing new insights for A2ARs regulation of neuronal differentiation and axonal regeneration.
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.
authors.forename: Filipa F
authors.initials: FF
authors.lastname: Ribeiro
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Neves-Tomé
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.
authors.forename: Natália
authors.initials: N
authors.lastname: Assaife-Lopes
authors.affiliation: Nerve Regeneration Group, Instituto de Biologia Molecular e Celular, IBMC, Universidade do Porto, 4150-180, Porto, Portugal.
authors.forename: Telma E
authors.initials: TE
authors.lastname: Santos
authors.affiliation: iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1649-003, Lisbon, Portugal.
authors.forename: Rui F M
authors.initials: RF
authors.lastname: Silva
authors.affiliation: iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1649-003, Lisbon, Portugal.
authors.forename: Dora
authors.initials: D
authors.lastname: Brites
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal.
authors.forename: Joaquim A
authors.initials: JA
authors.lastname: Ribeiro
authors.affiliation: Nerve Regeneration Group, Instituto de Biologia Molecular e Celular, IBMC, Universidade do Porto, 4150-180, Porto, Portugal.
authors.forename: Mónica M
authors.initials: MM
authors.lastname: Sousa
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal. anaseb@medicina.ulisboa.pt.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisbon, Portugal. anaseb@medicina.ulisboa.pt.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sebastião
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D020813:Receptor, trkB / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D019208:Brain-Derived Neurotrophic Factor; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D020813:Receptor, trkB; D000241:Adenosine
keywords: Axonal growth; BDNF; Cortical primary cultures; Microtubule dynamics; Neurite outgrowth