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Determination and mechanisms of trauma-induced glial cell death in the developing chick central nervous system McBride, Christopher Barry


Traumatic injuries to the central nervous system can lead to debilitating and often irreversible neurological deficits, which result from a poorly understood, multifactorial degenerative response. Although the initial cellular damage incurred by the traumatic event is instantaneous, a secondary, protracted degenerative phase can greatly exacerbate tissue damage and functional impairment. A recently described feature of this secondary response is the delayed apoptotic death of white matter oligodendrocytes remote from the lesion. This highly regulated, stereotyped form of cell death is thought to be executed by the caspase family of intracellular proteases. To investigate the role of caspases in injury-induced oligodendrocyte apoptosis, I developed an in vivo model of spinal cord injury in the developing chick embryo. Increased developmental apoptosis in the cervical spinal cord was observed in the cervical white matter between embryonic days 13-18, which correlated with the period of myelination of the spinal cord. Following transection during this period, a large increase in apoptotic cells was detected primarily in the ventrolateral and ventromedial white matter for several spinal cord segments caudal to the injury. Double labeling of apoptotic cells with cell specific antibodies revealed a large number of the dying cells to be oligodendrocytes but not astrocytes. In ovo application of caspase inhibitors significantly attenuated the transection-induced apoptotic response in the white matter remote from the lesion, but did not affect developmental apoptosis. Caspase-3-like catalytic activity was a component of the apoptotic response in this region following transection, and immunostaining for the active form of caspase-3 revealed its presence in an increased number of cells following injury. All cells expressing activated caspase-3 were apoptotic, and were distributed in the same region of spinal cord white matter as apoptotic oligodendrocytes. These results indicate oligodendrocytes undergo a period of heightened sensitivity to traumatic injury that correlates with the period of developmental oligodendrocyte apoptosis and with myelination of the spinal cord, and that caspases appear to mediate their death after trauma. The embryonic chick model of neurotrauma developed in this thesis may be used to further understand the mechanisms of oligodendrocyte death and survival in degenerative conditions characterized by oligodendrocyte apoptosis.

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