Neuronal Loss and Plasticity in Epilepsy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Abstract A severe brain insult such as status epilepticus or traumatic brain injury has the potential for producing epilepsy later in life. However, a latent period often occurs between the initial insult and the appearance of spontaneous seizures or epilepsy. The current studies are designed to identify the progressive morphological and biochemical changes that occur following status epilepticus in a mouse model of temporal lobe epilepsy and following traumatic brain injury. Emphasis will be placed on potential changes in chloride transporters that play a major role in regulating neuronal excitability. Immunohistochemical methods with light and confocal microscopy will be used in studies of each model to determine the sequential changes. The first group of studies will identify the normal localization of the two major chloride transporters in the hippocampus and other brain regions that are often involved in temporal lobe epilepsy. A second group of studies will test the hypothesis that expression of the chloride transporters is altered in a mouse model of epilepsy at several time points. These studies will include analyses at short intervals after status epilepticus; during the latent period before spontaneous seizures develop; during the chronic period; and immediately after a spontaneous seizure. The broad hypothesis is that the chloride transporters will be altered in ways that could reduce the effectivenss of GABAergic inhibition in the pilocarpine-treated animals and thus contribute to the development of epilepsy and the initiation of spontaneous seizures. The third group of studies will test the hypothesis that blocking the chloride transporter responsible for moving chloride into neurons will reduce seizure-induced damage of vulnerable neurons in the dentate gyrus. The final group of studies will test the hypothesis that genetic alterations of the GABA system or a chloride transporter can increase hippocampal damage following a mild to moderate traumatic brain injury. The broad goals of the studies are to identify progressive changes that could promote the development of epilepsy following status epilepticus or head trauma and thus provide a basis for designing treatments to prevent such changes.