Studies proposed are based on the premise that recurring seizures in early-life contribute to cognitive deficits in children suffering from intractable epilepsy. Recent results from several animal models have shown that adult rats are learning impaired after they have experienced recurrent seizures in infancy. These spatial learning deficits do not appear to be the product of cell death although our laboratory has reported a loss of dendritic spines on hippocampal pyramidal cells. Consistent with this latter result are more recent findings demonstrating a persistent decrease in the expression of both NMDA and AMPA receptor subunits in the hippocampus of rats that have experienced seizures in infancy. These results suggest that recurrent seizures may induce compensatory or homeostatic mechanisms in the developing brain in an attempt to decrease the frequency and intensity of subsequent seizures. However, since NMDA receptors are intimately involved in processes responsible for learning and memory, these homeostatic mechanisms may also impair learning. To study the cellular and molecular mechanisms responsible for NMDA receptor downregulation, an in vitro model of developmental epilepsy has been developed that closely reproduces the changes in NMDA and AMPA receptor subunit expression seen in vivo. Using this model, results show that NMDA and AMPA mEPSCs are also reduced in amplitude and the expression ofmRNA for the NMDA receptor subunits NR2A and NR2B are downregulated following chronic seizure-like activity. Experiments proposed will chart the developmental time course of these effects since preliminary results have also shown that an upregulation in gene expression occurs prior to receptor subunit downregulation. Other studies will examine presynaptic contributions to diminished synaptic transmission. Changes in the metabolic half-life of receptor subunit proteins will also be measured. Finally, experiments will begin to identify the signaling cascades responsible for the seizure-induced downregulation of NMDA receptor subunit gene expression. By identifying these pathways, novel therapies may eventually be developed to prevent NMDA receptor downregulation and hopefully prevent the learning deficits produced by recurring seizures in infancy.
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