Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination

Laura Jane Oluich, Jo Anne S. Stratton, Yao Lulu Xing, Sze Woei Ng, Holly S. Cate, Pankaj Sah, François Windels, Trevor J. Kilpatrick, Tobias D. Merson

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68 Citations (Scopus)

Abstract

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ~26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary,wehave shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted.

Original languageEnglish
Pages (from-to)8317-8330
Number of pages14
JournalJournal of Neuroscience
Volume32
Issue number24
DOIs
Publication statusPublished - 13 Jun 2012
Externally publishedYes

Cite this

Oluich, Laura Jane ; Stratton, Jo Anne S. ; Xing, Yao Lulu ; Ng, Sze Woei ; Cate, Holly S. ; Sah, Pankaj ; Windels, François ; Kilpatrick, Trevor J. ; Merson, Tobias D. / Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 24. pp. 8317-8330.
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Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination. / Oluich, Laura Jane; Stratton, Jo Anne S.; Xing, Yao Lulu; Ng, Sze Woei; Cate, Holly S.; Sah, Pankaj; Windels, François; Kilpatrick, Trevor J.; Merson, Tobias D.

In: Journal of Neuroscience, Vol. 32, No. 24, 13.06.2012, p. 8317-8330.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Oluich, Laura Jane

AU - Stratton, Jo Anne S.

AU - Xing, Yao Lulu

AU - Ng, Sze Woei

AU - Cate, Holly S.

AU - Sah, Pankaj

AU - Windels, François

AU - Kilpatrick, Trevor J.

AU - Merson, Tobias D.

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