Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination.
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, we have 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.
Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria 3010, Australia.
Laura-Jane
LJ
Oluich
Jo Anne S
JA
Stratton
Yao Lulu
YL
Xing
Sze Woei
SW
Ng
Holly S
HS
Cate
Pankaj
P
Sah
François
F
Windels
Trevor J
TJ
Kilpatrick
Tobias D
TD
Merson
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002452:Cell Count / Q000379:methods / Q000706:statistics & numerical data; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D004167:Diphtheria Toxin / Q000633:toxicity; D004195:Disease Models, Animal; D005073:Evoked Potentials, Somatosensory / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000473:pathology* / Q000648:ultrastructure; D009474:Neurons / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
D004167:Diphtheria Toxin; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins