Over the past 5 years, we have focused on studies aiming at understanding the response and adaptation of brainstem neurons to O2 deprivation. Our results have indicated that the response of brainstem neurons to hypoxia is different from that of cortical neurons. During hypoxia, brainstem neurons depolarize and increase their excitability to raise motoneuronal output, while excitability of cortical neurons decreases. This decrease in neuronal excitability may delay injury in cortical neurons, but it is not clear how brainstem neurons protect themselves from excessive depolarization and hypoxic damage. In this regard, our preliminary data have shown that activation of ATP-sensitive K+ (Katp) channels occurs during hypoxia and this may attenuate the hypoxia-induced depolarization and limit the increased neuronal excitability. We believe that this is an important finding as its implications are not limited only to brainstem neurons, but also applied to all neurons that are endowed with these channels. In spite of this, Katp channel regulation in central neurons is not well understood, especially during hypoxia. In order to determine the role of these Katp channels during O2 deprivation and their regulation by a number of cytosolic and membrane factors, we have developed this experimental proposal. Three major hypotheses will be tested: 1) hypoxia activates Katp channels in brainstem neurons and this improves the functional recovery of these neurons post hypoxia; 2) activation of Katp channels during hypoxia is a result of interactive changes in several cytosolic and membrane factors; and 3) Katp channel activity is modulated by endogenous neurotransmitters in a G protein-dependent manner. Several techniques will be used including single channel recordings in excised and cell-attached patches, whole-cell voltage clamp in acutely dissociated neurons, measurements of ionic concentrations with ion-selective microelectrodes and intracellular recordings from brainstem slices. All of these techniques are currently operative in our laboratory. Two groups of neurons (hypoglossal neurons and non-respiratory neurons in the substantia nigra) will be used in these experiments, both of which have a high density of Katp channels. We believe that our proposed studies will yield important new information that will improve our understanding of how these Katp channels are regulated in central neurons at zest and during hypoxia. We wish that this new knowledge will lead to a design of more effective therapeutical strategies in preventing or diminishing hypoxia/ischemia- induced brain injury.
Showing the most recent 10 out of 33 publications
