Combined, glial cells and extracellular space (ECS) occupy over 50% of the volume of the nervous system. Derangement in their function may possibly play important roles in clinical entities such as epilepsy, some cancers, migraine headaches, and certain psychiatric problems. However, neither glia nor ECS has received significant study compared to neurons. The research proposed here will explore the topics of ECS and glial cell function in the vertebrate retina. The retina is essentially a part of the central nervous system, and information gained by these experiments will be of value not only to vision scientists, but also to neuroscientists in general. The structure of retinal ECS will be determined by high-pressure freezing and electron microscopy, and also by the use of fluorescently tagged molecules. The ionic composition of ECS will be examined with ion- selective microelectrodes, and possibly with fluorescent indicator dyes. Activity-induced changes in ECS volume will be assessed by measurements of probe ions and of tissue resistance. The origins of field potentials will be studied by using current source density analysis. Light-evoked increases in extracellular K+ are cleared from ECS in part by spatial buffering through glial cells. Spatial buffering will be tested for the case of K-decreases. The magnitude of this buffering will be compared to the effectiveness of other clearance mechanisms. Agents will be tested that might interfere with specific aspects of Muller cell function. There will be an attempt to selectively damage Muller cells by complement-induced immunolysis. If successful, then a set of experiments is planned to test various aspects of the retinal function in the absence of normal Muller cells.
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