The goal of this project is to identify regulatory processes that enable neurons to tolerate and recover from cerebral hypoxia or ischemia. The project will focus on processes that actively regulated calcium influx through neuronal glutamate receptor ion channels, because calcium influx through neuronal glutamate receptor ion channels, because calcium influx via these channels may cause cell death from hypoxia or ischemia. We proposed to test the hypothesis that a regulated decrease in glutamate receptor ion channel activity occurs in naturally hypoxia-tolerant neurons and serves to stabilize cytosolic free calcium concentration. This concept of """"""""ion channel arrest"""""""" is based on preliminary data that suggests that the hypoxia-tolerant central nervous systems of newborn rats and freshwater turtles have in common a significant hypoxia-induced resistance to accumulation of cytosolic free calcium. Furthermore, we will test whether a similar partial """"""""arrest"""""""" of glutamate-mediated excitatory neurotransmission is caused by general anesthetics. Experiments are planned to address the following questions: 1. Do hypoxia-tolerant neurons avoid cytosolic calcium accumulation by """"""""arresting"""""""" glutamate receptors ion channels? 2. Does adenosine or protein kinase C regulate glutamate receptor arrest during hypoxia? 3. Do volatile general anesthetics cause an arrest of glutamate- activated calcium influx, and does this limit cytosolic calcium accumulation during hypoxia/ischemia? Answers to these questions will be important from several perspectives. First, they will identify new strategies for protecting neurons from the deleterious effects of hypoxia, ischemia and neurodegenerative diseases caused by glutamate excitoxicity. Second, they will identify why the adult brain, unlike the neonate, is incapable of avoiding neurotoxicity from hypoxia-induced glutamate release. Finally, they may provide a basis for more completely understanding the neuroprotective effects of some anesthetics, and help guide the development of new anesthetics with improved potential for cerebral protection.
