Epilepsy is a common and disabling condition that frequently begins in infancy and childhood. The cellular and molecular changes that underlie the development of epilepsy (epileptogenesis) are not fully understood. GABAA receptors (GABARs) are the most abundant inhibitory neurotransmitter receptors in forebrain, and several lines of evidence indicate that alterations in these receptors may play a critical role in epileptogenesis. During the initial funding period of this grant, we demonstrated long-term, age-specific changes in expression of GABAR subunits in hippocampal dentate granule neurons (DGNs) following lithium-pilocarpine induced status epilepticus (SE) during early postnatal development. To fully understand the importance of these GABAR alterations in developmental epileptogenesis, however, we must determine 1) if these changes precede development of epilepsy or are a response to ongoing seizure activity, 2) if these changes occur in other developmental models of epilepsy and other regions of the hippocampus, and 3) if these changes are a critical determinant of later epilepsy development. In our first competitive renewal, studies are proposed to address these three fundamental questions. We will determine whether SE-induced changes in GABAR subunit expression precede or follow onset of epilepsy and if manipulation of GABAR subunit expression alters the frequency of epilepsy development. We will also expand our studies to examine GABAR subunit expression following early-life SE in two additional developmental epilepsy models (kainic acid-induced seizures and hyperthermia-induced seizures) and in three different regions of the hippocampus (CA1 and CA3 regions in addition to dentate gyrus). The proposed studies are expected to provide evidence that hippocampal GABAR subunit changes occur in a variety of developmental epilepsy models, precede onset of spontaneous seizures and play a critical role in the process of epileptogenesis after early-life SE. Results of these studies should advance our understanding of the role of GABAR changes in developmental epileptogenesis and facilitate development of new therapies for the prevention or cure of epilepsy after early-life insults by identifying potential new therapeutic targets. ? ?
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