Prolonged hypoxia may lead to serious neuronal dysfunction, sublethal injury or cell death in the cortex during development. A number of neurological diseases in the young (e.g., epilepsy and cerebral palsy) have been attributed to the occurrence of hypoxic episodes in early life. It is important, therefore, to understand the effect of low 02 for short and prolonged periods on neuronal activity and its underlying mechanisms. Although there are considerable data pertaining to the effect of acute hypoxia on neurons, there is little known about neuronal excitability and membrane properties during chronic hypoxia, especially during development. Our group has focused on the regulation of neuronal responsiveness to prolonged 02 deprivation in immature and developing cortical neurons and made several new observations. These include 1) chronic hypoxia renders immature neurons more susceptible to subsequent stress than naive ones; 2) chronic hypoxia up-regulates Na+ channels in immature brain at both mRNA and protein levels; 3) Na+ channel subtypes are differentially expressed in the cortex during development; 4)chronic hypoxia selectively up-regulates expression of Na+ channel type III with slight or no change in other types of Na+ channels and 5) Na+ channel blockers greatly attenuate the enhanced susceptibility to subsequent stress in chronic hypoxia-exposed neurons. These results suggest that the hypoxia-induced Na+ channel expression may have direct bearing on abnormal neuronal discharge in young patients with epilepsy induced by hypoxic insult in early life. Our recent data further suggest that the hypoxia-induced Na+ channel up-regulation is attenuated by delta-opioid receptor (DOR) activation. Based on these preliminary data, the general hypothesis is as + __________________ follows: Prolonged 02 deprivation increases the neuronal responsiveness to subsequent stress in the immature neocortex and this is related causally to an up-regulation of specific Na+ channel subtypes; this up-regulation can be prevented by activating DOR and its signaling pathways. Using multiple techniques including electrophysiologic, transgenic and molecular approaches, the aims of this grant is to test the following specific hypothesis: 1) Chronic hypoxia selectively regulates the expression of Na+ channel type III in the immature cortex at a transcriptional and/or translational level; 2) Na+ channel III transgenic over-expression mimics responses obtained in neurons with chronic hypoxia; and 3) Chronic hypoxia-induced Na+ channel expression can be prevented by activating DOR and its kinase pathways. This application will largely improve our understanding of neuronal responses to prolonged hypoxia and the molecular mechanisms and shed light on alternative solutions for hypoxic/ischemic brain injury and the related neurological diseases.
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