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.
Relevance to Veterans Health Status epilepticus as well as other acute brain insults, such as head trauma, are serious health problems that affect many Veterans. Although the causes may vary, a concern in each case is the possible development of epilepsy following recovery from the initial brain insult. Basic research is needed to identify progressive changes in the brain that occur following the injury in order to develop preventive treatment. The studies will focus on changes in the GABA system, a major neurotransmitter system in the brain, and chloride (Cl-) transporters that control the level of intracellular Cl- and thus help determine how effective the GABA system will be in controlling seizure activity. The goal of the proposed studies is to identify underlying factors which could contribute to loss of neurons and seizure development following status epilepticus and traumatic brain injury. Identifying such factors could lead to the development of new treatment strategies.
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