The specific focus of this proposal is to investigate age-specific mechanisms of perinatal hypoxic encephalopathy, the most common cause of neonatal seizures and brain injury in the human infant. Hypoxia-induced seizures in the perinatal period can be refractory to therapy and can result in long-term neurological deficits and epilepsy. Using our in vivo and in vitro rodent models of perinatal hypoxia-induced seizures, we found that the AMPA receptor (AMPAR) subtype of glutamate receptors plays a crucial role in the age-specific vulnerability to this seizure type and in the long-term epileptogenic effects of perinatal hypoxia. We have shown that AMPAR antagonists block the acute and chronic epileptogenic effects of perinatal hypoxia. In addition, our preliminary electrophysiological and molecular data reveal a sequence of changes in function and expression of neurotransmitter receptors and signaling molecules. ? ? We aim to evaluate age-specific structural and functional changes in certain neurotransmitter receptors and signaling molecules with overall aim to identify age-specific molecular targets for the treatment of refractory perinatal seizures. ? ? Aim 1 will examine functional alterations contributing to the neuronal excitability observed at intervals after hypoxia in the perinatal rat. Extracellular and whole-cell recordings will be made from hippocampal slices from rats after hypoxia-induced seizures at P10 for comparison with littermate controls. In parallel, Aim 2 will evaluate hypoxia-induced alterations in glutamate and GABA receptors as well as the Ca++-regulated molecules CaMKII and calcineurin, which we have shown are altered at intervals following perinatal hypoxia.
Aim 3 will establish whether the subacute and long-term epileptogenic effects of hypoxia can be blocked by post-treatment with AMPAR antagonists or calcineurin blockers to assess their efficacy as therapeutic strategies. As the age window of vulnerability to hypoxia is one in which there is robust synaptogenesis, Aim 4 will determine if perinatal administration of AMPAR antagonists adversely alters AMPAR development. In the rat, the age window of vulnerability to perinatal hypoxia-induced seizures is characterized by relative overexpression of AMPARs and Ca++-permeable AMPARs compared to earlier and later developmental stages.
Aim 5 will test the human relevance of our data by examining maturational regulation of AMPARs before, during, and after the perinatal period in human fetal and infant postmortem cortical tissue.
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