Immature white matter is subject to ischemic injury during the development of the lesion called periventricular leukomalacia, which is the major pathology, associated with cerebral palsy. The goal of this research is to understand the mechanisms that underlie acute ischemic cell death in immature white matter glial cells. Fluorescent ion-sensitive dyes will be loaded into glial cells in the neonatal rat optic nerve and used to measure changes in intracellular [Ca2+], [Na+] and pH during ischemia in situ. These ionic changes will be correlated to the occurrence of cell death and any casual relationships will be determined. Ionic substitution and drug application will be used to probe mechanisms that underlie ionic derangements that occur in neonatal white matter glia during ischemia. Glial cell types within neonatal white matter are likely to show acute changes in intracellular ions during ischemia due to quite different mechanisms. Live staining of glia in situ will be applied to distinguish astrocytes from oligodendrocytes, allowing both the characteristics of cell death and ionic distribution during ischemia to be analyzed in the two major types of marcoglia present in the CNS. Experiments will test three hypotheses: 1) Acute ischemic astrocyte death at the point in development most at risk (P10nRON), results from Na+ -influx and cell swelling. 2) Na+ -influx/cell swelling also accounts for a significant proportion of acute death of oligodendrocytes and of less mature astrocytes. 3) Non-NMDA glutamate receptors mediate only a proportion of toxic Ca2+ -influx into oligodendroglial during ischemia.
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