Status epilepticus (SE), is a medical emergency associated with significant morbidity and mortality. It also is associated with permanent pathological sequella, including epilepsy. Very little is known about how SE may affect the properties of surviving neurons in the injured brain. Preliminary studies have demonstrated that, in hippocampal neurons, profound alterations in the expression of neurotransmitter receptor subunits occur in distinct patterns as an early consequence of SE. Since neurotransmitter receptor activation during synaptic activity is the critical mediator of hippocampal function, these cellular pathological sequella of SE may be the primary determinants of subsequent short- and long-term morbidity. The focus of this proposal is an examination of these effects. Studies are designed to specifically test our CENTRAL HYPOTHESIS: During and following SE, alterations in transcriptional regulation of neurotransmitter receptor expression fundamentally alters the phenotype of neurons within affected areas in a regional- and gene-specific manner, and this pathologically modifies hippocampal function. This hypothesis is to be tested in a series of experiments focused on 3 SPECIFIC AIMS:
AIM 1 : Examine the pathological functional consequences of SE-induced neurotransmitter receptor downregulation in dentate granule cells.
AIM 2 : Determine mechanisms mediating the downregulation of neurotransmitter receptor mRNA levels and function in dentate granule cells following SE.
AIM 3 : Determine the transcription factors and mechanisms of transcriptional repression of neurotransmitter receptor subunit genes in dentate granule cells following SE. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will attempt to thoroughly characterize 1) the mechanisms mediating SE-associated changes in the transcriptional production of neurotransmitter receptors, and 2) how these changes may contribute to the subsequent development of temporal lobe epilepsy, one of the most devastating permanent outcomes resulting from SE. Results from studies proposed in this application could significantly enhance our knowledge of physiological and molecular mechanisms mediating the brain's response to injury. Understanding of these processes is critical in developing novel, more effective strategies for controlling the deleterious pathological consequences of brain injury, including epilepsy. ? ?
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