Oligodendrocyte death and demyelination accompany many CNS insults, and these features are particularly prominent in spinal cord trauma. White matter injury, including demyelination, are the major cause of disability after spinal cord injury (SCI). Despite the clinical importance of this problem, the cellular and molecular mechanisms contributing to oligodendrocyte death are unclear. Since oligodendrocytes express functional AMPA-type glutamate receptors and elevated glutamate levels accompany SCI, we plan to explore the possibility that spinal cord oligodendrocytes are vulnerable to AMPA/kainate (KA) receptor-mediated excitotoxic death and examine whether this mechanism may contribute to the loss of oligodendrocytes and demyelination following SCI. Our preliminary data suggest oligodendrocytes, in vitro and in vivo, express functional AMPA/KA receptors, and are killed by AMPA/KA receptor overactivation. An initial characterization of the development, physiology and pathophysiology of AMPA/KA receptors will be completed in pure cultures of oligodendrocytes isolated from adult rodent spinal cord. Our preliminary data in vivo raise the specific possibility that a delayed and protracted excitotoxicity may contribute, in part, to the delayed oligodendrocyte death following SCI. If verified by these studies, this would be a novel and important concept in our understanding of the mechanisms of oligodendrocyte death, extending the excitotoxicity hypothesis to include non-neuronal cells and involvement in delayed mechanisms of SCI. The ultrastructural features and temporal pattern of oligodendrocyte death following SCI will be assessed using contusion and dorsal hemisection injury in adult rodents. Parallel studies using long term culture of intact brain and spinal cord will be carried out to investigate the mechanisms of oligodendrocyte death in the absence of factors complicating in vivo studies. We will further examine whether oligodendrocyte death and demyelination are reduced and the functional outcome improved by strategies designed to ameliorate AMPA/KA receptor excitotoxicity. The ultimate goal of this project is to enhance functional recovery after SCI, by understanding and limiting oligodendrocyte death and demyelination.
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