Axonal dysfunction as a result of persistent demyelination has been increasingly appreciated as a cause of functional deficit in demyelinating diseases such as multiple sclerosis. Therefore, it is crucial to understand the ultimate causes of ongoing axonal dysfunction and find effective measures to prevent axon loss. Our findings related to functional deficit and functional recovery of axons from a demyelinating insult are important preliminary steps towards understanding this issue. Cuprizone diet for 3-6 wks triggered extensive corpus callosum (CC) demyelination, reduced axon conduction, and resulted in loss of axon structural integrity including nodes of Ranvier. Replacing cuprizone diet with normal diet led to regeneration of myelin, but did not fully reverse the conduction and structural deficits. A shorter 1.5 wk cuprizone diet also caused demyelination of the CC, with minimal loss of axon structure and nodal organization. Switching to normal diet led to remyelination and restored callosal axon conduction to normal levels. Our findings suggest the existence of a critical window of time for remyelination, beyond which demyelinated axons become damaged beyond the point of repair and permanent functional loss follows. Moreover, initiating remyelination early within the critical period, before prolonged demyelination-induced axon damage ensues, will improve functional axon recovery and inhibit disease progression.
Pubmed ID: 19800949 RIS Download
Mesh terms: Action Potentials | Animals | Astrocytes | Axons | Cell Adhesion Molecules, Neuronal | Cell Lineage | Corpus Callosum | Cuprizone | Diet | Female | Kv1.2 Potassium Channel | Mice | Mice, Transgenic | Microglia | Myelin Sheath | NAV1.6 Voltage-Gated Sodium Channel | Nerve Tissue Proteins | Oligodendroglia | Ranvier's Nodes | Regeneration | Sodium Channels
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