The proposed research represents a continuation of studies, in vitro, of some of the basic physiological and morphological properties of mammalian glia and neurons, in relation to the ionic and volume regulation of the extracellular space (ECS) of brain. The long term goals of this work are to discover how the basic properties of glia and neurons interact to account for the dynamic, but regulated, ionic and volume flucuations seen in the ECS with brain activity. A new direction for this proposal is to study this issue in a pathological circumstance; specifically, to analyze the pathophysiology of anoxia in white matter of the brain, in mature and developing animals, using the isolated rat optic nerve (RON). Isolated RONs, tissue slices from rat cortex, and cultured astrocytes, will be used in most experiments and offer several advantages over in vivo preparations, including ready access of perfusion solutions to the ECS, direct visualization of microanatomic features of the tissue cells, and great experimental flexibility. Using standard electrophysiological recording techniques, ion-sensitive microelectrodes, and the patch-clamp method, the following projects will be undertaken: 1) developmental study of glial cell physiology and morphology in the RON; 2) patch-clamp studies of single ion channels in cultured glia; 3) analysis of activity dependent and K+ - induced changes in pHo in the RON and cortex; 4) studies on the pathophysiology of anoxia in white matter, using the RON; 5) studies on the mechanism(s) of neural activity dependent and K+ - induced ECS shrinkage; 6) developmental studies on the susceptibility of white matter to anoxic injury. These studies should provide basic new information about the properties of glia and neurons, especially as these relate to ion homeostasis in brain ECS under normal and pathological conditions. These studies are broadly relevant to the clinical problems of stroke, neonatal asphyxia, and brain swelling.
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