Physiological factors which influence the initiation and cessation of cortical epileptic discharge are important in understanding the pathophysiology of this process. Extracellular ion concentrations in the brain influence neuronal behavior and could serve as modulators of epileptic discharge; in fact, this has been shown to be the case for extracellular [K+]. Extracellular pH (pHo) has recently been shown to directly influence neuronal excitability and to modulate the action of excitatory neurotransmitters at the N-methyl D-Aspartate (NMDA) receptor; specifically, acid shifts decrease excitability and block NMDA currents. Furthermore, large and long-lasting changes in pHo occur with intense neural activity. Activity-dependent pHo shifts in the acid direction appear to be mediated, at least in part, by glial cells. These observations prompt the hypotheses that epileptic discharge is influenced by pHo and that activity-dependent extracellular acidification, mediated in part by glial cells, acts as a negative feedback mechanism to inhibit epileptic discharge. These hypotheses will be tested using neocortical and hippocampal brain slices and ion-sensitive microelectrodes. The role of glial cells in mediating extracellular acidification will be studied using ion-sensitive microelectrodes and the 'pure glial' rat optic nerve. Aspects of intracellular pH regulation that might contribute to extracellular acidification will be analyzed in cultured glial cells and neurons using microfluorometry. The proposed research represents a continuation of studies on the basic physiological properties of mammalian glial cells, in relationship to the ionic and volume regulation of brain extracellular space. These studies will provide useful new information about the mechanisms of pHo fluctuations in the brain while assessing the importance of pHo as a modulator of the excessive neural activity seen in epilepsy.
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