Molecular basis of the axon-oligodendrocyte interaction during remyelination

Multiple sclerosis is an autoimmune demyelinating disease affecting 2.5 million people worldwide. The disease is characterized by multifocal inflammation, oligodendrocyte death, reactive gliosis, and axonal degeneration. Lesions are usually found in the white matter of the brain and spinal cord. Nevertheless lesions have also been often recorded in gray matter areas of the brain such as the hippocampus. Demyelinated plaques in the hippocampus have been linked to cognitive deficits observed in 25-60% of multiple sclerosis patients. Cuprizone is a copper chelator which when administered to rodents reproducibly causes oligodendrocyte death and induces prominent demyelination in the corpus callosum within weeks. Remyelination occurs spontaneously after cuprizone is withdrawn from the rodent chow. Administration of cuprizone is thus used as a reliable animal model in studying demyelination as well as remyelination. Previous studies have shown that the hippocampus is also affected by cuprizone administration. In this study we described in detail hippocampal demyelination in the cuprizone model. We showed that after 6 weeks of 0.2% cuprizone treatment in C57BL/6 mice hippocampal demyelination was prominent. Also, distinct formations within the hippocampus had a variable temporal demyelination pattern. Demyelination in the hippocampus was accompanied by accumulation of astroglia, microglia, as well as accumulation of nestin-positive cells. Spontaneous remyelination has been described in multiple sclerosis plaques, and it has been found to restore electrophysiological activity. Remyelination requires first recruitment of oligodendrocyte precursor cells and later differentiation of these into mature oligodendrocytes. The neural cell adhesion molecule (NCAM) is playing a major role in cell-cell recognition in the nervous system. Its function is regulated by posttranslational addition of polysialic acid (PSA) on it by two polysialyltransferases, St8siaII and St8siaIV. St8siaIV is the enzyme predominantly active in adult mice. PSA regulates NCAM function by disrupting its adhesive properties. PSA is widely expressed during development, but its expression is limited to very few brain formations in adulthood. Its re-expression on permanently demyelinated axons in multiple sclerosis lesions renders PSA a possible remyelination inhibitor. We showed that cuprizone treatment affects PSA expression in the brain. More particularly a 6-week cuprizone administration leads to reduction of PSA expression in the fibers of the mossy fiber tract, while it completely disappears from fibers of the hippocampal commissure and from the young neurons of the subgranular cell layer of the dentate gyrus. To further study the role of PSA in remyelination, St8siaIV deficient mice were submitted to cuprizone treatment. We observed that reduced PSA synthesis is associated with a faster onset of remyelination in the corpus callosum and the cortex after withdrawal of the cuprizone treatment. This data show that PSA modulates demyelination in vivo and thus it could serve as a target for new regenerative treatments for multiple sclerosis.