For a number of years, we have been interested in neuronal excitability, its maturation in early life and its ionic basis in neurons in the brainstem, hippocampus and neocortex. In particular, we have recently focused our efforts on how nerve cells in the neonate and mature animal respond and adapt to O2 deprivation and ischemia. We have discovered in the past few years that there is a tight link between intermediary metabolism and channel gating and neuronal excitability in central neurons during metabolic stress. For example, the voltage-sensitive Na+ channel steady state availability is decreased in a major way when neocortical cells are deprived of O2 and that this is dependent on the presence of ATP. In addition and of regions in the CNS but are of high density in the neocortex of the rat and man, as assessed by labelled glibenclamide binding experiments. Because we have recently shown in preliminary form data suggesting that these receptors/channels play an important role in the anoxic response in nerve cells, we propose in this application 3 hypotheses: 1) KATP channels are a major factor in nerve cell function during acute graded hypoxia and recovery from hypoxia and this role is enhanced with maturation and by exposing animals to periods of hypoxia or ischemia; 2) Neocortical neurons in human brain rely also on KATP during O2 deprivation and 3) the brain KATP channel is structurally different from the recently cloned renal epithelial one. All the techniques needed for the slice preparation, the study of dissociated cells using patch clamp techniques and for the cloning of the brain channel in the human and in the rat are operative in our laboratory. We believe that information forthcoming from these experiments will be very important in our quest for understanding the physiologic and biologic sequence of events that take place with O2 deprivation or ischemia and, more importantly, to enhance our ability to manipulate the system and be able to promote hypoxia-resistance of nerve cells in the young and more mature human. This project will have strong interactions with Projects 2, 4 and 5 of the proposed Center grant as we will share not only equipment and facilities but also concepts and results that will benefit subsequent protocols and data interpretation.
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