The Epileptogenic Effect of Perinatal Hypoxia

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DESCRIPTION (provided by applicant): The highest incidence of seizures across the lifespan occurs in the neonatal period, and seizures in early life are associated with later life epilepsy, and significant neurocognitive and behavioral deficits. Our prior studies have shown that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPAR) subtype of the excitatory glutamate receptor is highly expressed in the rodent and human brain throughout the neonatal period, and is a critical mediator of the later epilepsy and behavioral comorbidities. The present proposal extends these studies and provides better preclinical assay systems for analysis of epileptogenesis and neurobehavior in both the rat and mouse model (Aim 1). We aim to better understand the mechanisms of seizure-induced alterations in network plasticity in order to identify reversible changes (Aim 2). Thus, we will extend our studies on the consequences of seizure-induced modifications of mammalian target of rapamycin (TOR) and Fragile X mental retardation protein (FMRP) pathways, and investigate the extent that brief pharmacologic manipulation of these pathways will decrease later life epilepsy and neurobehavioral deficits (Aim 3). Finally, we will study human tissue to determine whether there is evidence of dysregulation of AMPARs, mTOR or FMRP pathways in human brain tissue from neonates and infants with epilepsy (Aim 4). The overall goal of this ongoing research program is to identify mechanisms whereby this common form of seizures may induce later life epilepsy, cognitive and neurobehavioral deficits, including autism. The emphasis is on identifying therapeutic targets, preclinical disease modifying trials with clinically relevant outcomes, and validating these targets in human tissue to pave the way for translation clinical investigation.