title: Epsilon toxin from Clostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination.
abstract: Epsilon toxin (ET) is produced by Clostridium perfringens types B and D and causes severe neurological disorders in animals. ET has been observed binding to white matter, suggesting that it may target oligodendrocytes. In primary cultures containing oligodendrocytes and astrocytes, we found that ET (10(-9) M and 10(-7) M) binds to oligodendrocytes, but not to astrocytes. ET induces an increase in extracellular glutamate, and produces oscillations of intracellular Ca(2+) concentration in oligodendrocytes. These effects occurred without any change in the transmembrane resistance of oligodendrocytes, underlining that ET acts through a pore-independent mechanism. Pharmacological investigations revealed that the Ca(2+) oscillations are caused by the ET-induced rise in extracellular glutamate concentration. Indeed, the blockade of metabotropic glutamate receptors type 1 (mGluR1) prevented ET-induced Ca(2+) signals. Activation of the N-methyl-D-aspartate receptor (NMDA-R) is also involved, but to a lesser extent. Oligodendrocytes are responsible for myelinating neuronal axons. Using organotypic cultures of cerebellar slices, we found that ET induced the demyelination of Purkinje cell axons within 24 h. As this effect was suppressed by antagonizing mGluR1 and NMDA-R, demyelination is therefore caused by the initial ET-induced rise in extracellular glutamate concentration. This study reveals the novel possibility that ET can act on oligodendrocytes, thereby causing demyelination. Moreover, it suggests that for certain cell types such as oligodendrocytes, ET can act without forming pores, namely through the activation of an undefined receptor-mediated pathway.
authors.affiliation: Centre National de la Recherche Scientifique Associé à l'Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives UPR3212, 5 rue Blaise Pascal, Strasbourg, cedex F-67084, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Wioland
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dupont
authors.forename: Frédéric
authors.initials: F
authors.lastname: Doussau
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gaillard
authors.forename: Flavia
authors.initials: F
authors.lastname: Heid
authors.forename: Philippe
authors.initials: P
authors.lastname: Isope
authors.forename: Serge
authors.initials: S
authors.lastname: Pauillac
authors.forename: Michel R
authors.initials: MR
authors.lastname: Popoff
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Bossu
authors.forename: Bernard
authors.initials: B
authors.lastname: Poulain
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000382:microbiology / Q000473:pathology; D003016:Clostridium perfringens / Q000502:physiology*; D003711:Demyelinating Diseases; D018698:Glutamic Acid / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D051381:Rats
chemical_list: D001427:Bacterial Toxins; C039811:Clostridium perfringens epsilon-toxin; D018698:Glutamic Acid; D002118:Calcium