The regulation of pH is critical for the normal operation of the brain, as numerous channels and enzymes are sensitive to small shifts in hydrogen ion concentration. Acid base status can be particularly important in brain injury, where it can play a determinant role in the manifestation of brain damage and the recovery of function. Normal electrical activity also results in large changes in interstitial and intracellular pH, of sufficient speed and magnitude to influence function. These pH shifts arise from specialized mechanisms in neurons and glia, and therefore display marked regional heterogeneity and stereotyped patterns. The objective of this study is to determine the mechanisms which govern the dynamic behavior of pH in the central nervous system and to elucidate the role of these processes in modulating neural function. This broad aim will be addressed by investigating the dynamics of activity-dependent pH shifts at both the cellular and regional level. The role of carbonic anhydrase in governing the interstitial buffering capacity will be a principal focus. These experiments on brain slices will utilize using new technologies that permit temporal resolution of pH shifts in the millisecond range. Combining this capability with established patch clamp methods will allow analysis of the pH change that directly modulate excitatory synaptic currents. At the level of the isolated cell, attention will be turned to the specific acid transport mechanisms of neurons and astrocytes. Neuronal studies will address the relationship between calcium influx and the generation of interstitial alkaline shifts. Experiments on astrocytes will focus on the role of these cells as regulators of interstitial pH. The investigation will benefit from the combination of novel fluorescence and ion-selective microelectrode methods, capable of resolving real time changes in pH, bicarbonate, and carbon dioxide tension. These studies will provide an understanding of the functional role of hydrogen ions and add insights into the pathophysiology of pH regulation following stroke and cardiac arrest.
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