Epileptogenicity in the Developing Brain

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DESCRIPTION (provided by applicant): Children with epilepsy have more cognitive and psychiatric difficulties than children with other chronic illnesses. Pediatric neurologists are acutely aware of the distinctive manner in which the immature brain responds differently to a variety of insults as well as to therapeutic interventions. In March of 2000, NINDS coordinated a White House-initiated conference on "Curing Epilepsy" that identified interrupting the process of epileptogenesis as the number one agenda. The need for discovering the range of anatomic, physiological, and molecular substrates associated with the epilepsies and defining unambiguous markers of epileptogenicity was set as a major priority at that conference. The research proposed here has two goals, linked by the theme of the consequences of seizures on the developing brain. Specifically, this study will focus on (1) seizure-induced brain injury, and (2) the resulting alterations in structure and function of the developing brain that are epileptogenic. In studying seizure induced brain injury, the proposed work aims to determine the influence of (a) the developmental stage of the animals and (b) the duration of status epilepticus, that may constitute a threshold for injury. Mechanisms of cell-death (necrotic versus programmed cell death) will be studied as a function of these variables. The study will seek to isolate distinct processes critical in producing neuronal injury that may become evident during the course of status epilepticus. Animals will be observed over several months for the development of chronic spontaneous seizures, i.e. epilepsy, after the initial bout of status epilepticus, in order to determine the threshold duration of status epilepticus that is epileptogenic, and how this is modified by the developmental stage of the brain. These animals will be studied for anatomic (evidence of mossy fiber sprouting in the hippocampus) and physiologic (population spike amplitude and EPSP slope) alterations that accompany the onset and progression of epilepsy after a bout of status epilepticus during development. Our findings will provide the basis for future neuroprotective interventions targeting the developing brain at different stages of status epilepticus in order to interrupt the course of the epileptogenic process.