TY - JOUR
T1 - Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination
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.
PY - 2012/6/13
Y1 - 2012/6/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862265936&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1053-12.2012
DO - 10.1523/JNEUROSCI.1053-12.2012
M3 - Article
C2 - 22699912
AN - SCOPUS:84862265936
SN - 0270-6474
VL - 32
SP - 8317
EP - 8330
JO - The Journal of Neuroscience
JF - The Journal of Neuroscience
IS - 24
ER -