title: Excitotoxicity induced by kainic acid provokes glycogen synthase kinase-3 truncation in the hippocampus.
abstract: In neuronal cultures, glycogen synthase kinase 3(GSK3) is truncated at the N-terminal end by calpain downstream of activated glutamate receptors. However, the in vivo biological significance of that truncation has not been explored. In an attempt to elucidate if GSK3 truncation has a pathophysiological relevance, we have used intraperitoneal injections of kainic acid (KA) in rats and intra-amygdala KA microinjections in mice as in vivo models of excitotoxicity. Spectrin cleavage analyzed by immunohistochemistry was observed in the CA1 hippocampal field in KA-intraperitoneal treated rats while the CA3 region was the hippocampal area affected after intra-amygdala KA microinjections. GSK3β immunofluorescence did not colocalize with truncated spectrin in both treatments using an antibody that recognize the N-terminal end of GSK3β. Thus, those neurons which are spectrin-positive do not show GSK3β immunolabelling. To study GSK3β truncation in vitro, we exposed organotypic hippocampal slices and cultured cortical neurons to KA leading to the truncation of GSK3 and we found that truncation was blocked by the calpain inhibitor calpeptin. These data suggest a relationship between N-terminal GSK3β truncation and excitotoxicity. Overall, our data reinforces the important relationship between glutamate receptors and GSK3 and their role in neurodegenerative processes in which excitotoxicity is involved.
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC/UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, 28031 Madrid, Spain.
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Jurado-Arjona
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC/UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Goñi-Oliver
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC/UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Rodríguez-Prada
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen׳s Green, Dublin 2, Ireland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen׳s Green, Dublin 2, Ireland.
authors.forename: D C
authors.initials: DC
authors.lastname: Henshall
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC/UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, 28031 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Ávila
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC/UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, 28031 Madrid, Spain. Electronic address: fhernandez@cbm.csic.es.
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
mesh_terms: D000679:Amygdala / Q000187:drug effects; D000818:Animals; D000906:Antibodies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013049:Spectrin / Q000378:metabolism
chemical_list: D000906:Antibodies; D018690:Excitatory Amino Acid Agonists; D013049:Spectrin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D007608:Kainic Acid
keywords: Calpain; Excitotoxicity; Glycogen synthase kinase-3 (GSK3); Hippocampus; Kainic acid (KA); Proteolysis