title: Kainic acid triggers oligodendrocyte precursor cell proliferation and neuronal differentiation from striatal neural stem cells.
abstract: Glutamate is an excitatory amino acid that serves important functions in mammalian brain development through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/ kainate receptor stimulation. Neural stem cells with self-renewal and multilineage potential are a useful tool to study the signals involved in the regulation of brain development. We have investigated the role played by AMPA/kainate receptors during the differentiation of neural stem cells derived from fetal rat striatum. The application of 1 and 10 microM kainic acid increased significantly the phosphorylation of the cyclic AMP response element binding protein (CREB), raised bromodeoxyuridine incorporation in O4-positive oligodendrocyte precursors, and increased the number of O1-positive cells in the cultures. Increased CREB phosphorylation and proliferation were prevented by the AMPA receptor antagonist 4-4(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine (SYM 2206) and by protein kinase A and protein kinase C inhibitors. Cultures treated with 100 microM kainic acid showed decreased proliferation, a lower proportion of O1-positive cells, and apoptosis of O4-positive cells. None of these effects were prevented by SYM 2206, suggesting that kainate receptors take part in these events. We conclude that AMPA receptor stimulation by kainic acid promotes the proliferation of oligodendrocyte precursors derived from neural stem cells through a mechanism that requires the activation of CREB by protein kinase A and C. In the neurons derived from these cells, either AMPA or kainate receptor stimulation produces neuritic growth and larger cell bodies.
authors.affiliation: Servicio de Neurobiología, Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Redondo
authors.forename: Miguel A
authors.initials: MA
authors.lastname: López-Toledano
authors.forename: Maria V T
authors.initials: MV
authors.lastname: Lobo
authors.forename: Rafael
authors.initials: R
authors.lastname: Gonzalo-Gobernado
authors.forename: Diana
authors.initials: D
authors.lastname: Reimers
authors.forename: Antonio S
authors.initials: AS
authors.lastname: Herranz
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Paíno
authors.forename: Eulalia
authors.initials: E
authors.lastname: Bazán
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology* / Q000196:embryology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling / Q000379:methods; D007608:Kainic Acid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000187:drug effects* / Q000502:physiology; D010793:Phthalazines / Q000494:pharmacology; D051381:Rats; D013234:Stem Cells / Q000145:classification / Q000187:drug effects*
chemical_list: C487116:4-aminophenyl-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine; D017362:Cyclic AMP Response Element-Binding Protein; D018690:Excitatory Amino Acid Agonists; D010793:Phthalazines; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001973:Bromodeoxyuridine; D007608:Kainic Acid; D002118:Calcium