Seizure-induced Neuronal Loss and Epileptogenesis in the Immature Brain

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DESCRIPTION (provided by applicant): There is a controversy over whether neuronal death in the hippocampal formation is involved in the development of epilepsy after a brain insult in the immature brain. Several studies have reported that, unlike what is widely observed in adult animal models, immature animals can develop epilepsy without observable neuronal loss in the hippocampal formation. Two critical methodological issues directly related to this problem are: 1) whether anatomic methods for determining neuronal loss can detect injury that may be subtle or anatomically restricted to sub-regions of the hippocampus and 2) whether the different assays for epilepsy (changes in seizure threshold or seizure monitoring) accurately detect which animals have developed epilepsy. This project utilizes the lithium pilocarpine (LiPC) animal model of epilepsy, a well established model of chemoconvulsant status epilepticus (SE), to reexamine whether prolonged seizures result in the development of epilepsy in immature animals, and, in particular, whether neuronal death is associated with this process. We propose to use Flouro-jade B (a histochemical marker for acute neuronal injury), Nissl cell counting with unbiased stereology techniques, and magnetic resonance imaging of hippocampal volume as three independent methods for detecting potential neuronal injury and death. Animals will be monitored continuously with a wireless EEG telemetry system with video analysis of behavior to ensure an accurate assessment of which animals develop epilepsy. The strength of our approach is that a more meaningful correlation between neuronal injury, cell death, and the development of epilepsy can be made because our electrographic monitoring and anatomical analysis will be more complete than previous studies. Determining whether neuronal loss or other factors contribute to epileptogenesis in the immature brain is critical for understanding how children develop epilepsy after brain insult and will aid clinicians in developing novel interventions for treating and preventing this condition. This proposal outlines a structured supervised research experience that is critical for helping the applicant develop a long-term research career studying pediatric epilepsies. The plan has been developed with strong institutional support, and provides an excellent environment with mentored guidance from epilepsy researchers who have a long track record of training successful scientists. It is specifically designed to allow the applicant to acquire new research skills and transition into an independent clinical physician scientist. PUBLIC HEALTH RELEVANCE: Some researchers have claimed that, unlike what is commonly thought to occur in adults, children can develop the disorder of epilepsy after an insult to the brain without significant brain injury with loss of brain cells. We propose to use an animal model of epilepsy in young rats to induce them to have epilepsy, and then assess for evidence of neuronal injury and loss of neurons using three separate methods (Flouro-jade B-a chemical marker for injured neurons, actual counting of remaining neurons to see if they have been lost, and neuroimaging with magnetic resonance imaging). These experiments will help us better understand the relationship between neuronal injury/death and epilepsy and will provide information about what changes may occur when children get epilepsy.