The broad objective of this investigation is to elucidate the mechanisms which govern the intracellular pH of glial cells under resting, stimulated, and hypoxic conditions. The study of the relationship between brain electrical activity and glial intracellular pH will add new insights into the process of neuronal-glial signalling. In addition, characterization of the glial pH response to sustained electrical stimulation will provide information relevant to glial behavior during seizure activity. The investigation of glial pH regulation during tissue hypoxia will directly address current issues in ischemic brain pathophysiology. The project will have four specific aims. (1) Glial acid transport systems will be identified and their role in the regulation of glial intracellular pH will be determined. (2) The mechanisms underlying the modulation of glial intracellular pH during neuronal activity will be elucidated. (3) Activity- dependent extracellular pH transients will be related to concomitant glial intracellular pH shifts. (4) The response of glial intracellular pH to tissue hypoxia will be studied, and its relationship to glucose availability determined. The guinea pig olfactory cortical slice preparation will be used as an in vitro model system. The intracellular pH of cortical glial cells will be measured directly during continuous recording with double- barreled, pH-sensitive microelectrodes. Glial intracellular pH will be manipulated by acid-loading, stimulation of the lateral olfactory tract, and by exposure to oxygen-free media. Experiments will focus on the ionic-dependence and pharmacologic sensitivity of the pH modulatory and regulatory mechanisms.
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