Genetic susceptibility has been implicated in more than 40-50% of human epilepsies. However to date, only 12 genes have been associated with human epilepsy syndromes, and these can only account for less than 1% of epilepsy patients. Further identification of genes that are related to the pathogenesis of epilepsy is crucial to understand how epilepsies develop and could eventually lead to better treatment and prevention of the disease. We have generated a unique mutant animal model in which NMDA glutamate receptors are selectively knocked out in the cerebral cortex and hippocampus. Unlike standard NMDA knockout mutant mice that die soon after birth, our mutant mice survive many weeks but they develop seizure activity during late adolescence (3-6 weeks postnatal). A unique feature of this mutant is that this seizure activity develops in the absence of NMDA receptor mediated activity. Many animal models of epilepsy are based on an upregulation of NMDA activity, and thus our model may provide unique means of producing hyperexcitability leading to epileptiform activity independent of NMDA activity. Preliminary results suggest an important role of NMDA receptors in regulating the neuronal excitability during normal development; however, the mechanisms by which the selective lack of NMDA receptors in these mice leads to hyperexcitability and eventually spontaneous seizures is unknown. The goal of the proposed experiments is to investigate how the lack of NMDA receptors during development leads to altered neuronal excitability, and how this gives rise to seizure activity. We will use a multidisciplinary approach including molecular biological, genetic, anatomical, cellular and system neurophysiological, and behavioral techniques to understand the development of epileptogenesis in this unique animal model. We plan to extend our characterization of the spontaneous seizure phenotype to test our hypothesis with the following specific aims: 1. To determine whether and when during development seizure susceptibility to chemical convulsants is altered in the mutant mice. These results would provide a time line for the development of hyperexcitability within the neocortex. 2. To map out neural networks involved in seizure development and generation in the mutant mice by studying the expression of the immediate early gene, c-fos. 3. To determine how the balance between inhibition and excitation is altered in the mutant mice. We hypothesize that the excitatory drive onto interneurons is dominated by NMDA receptor actions in normal animals, and in these mutant mice the reduction of NMDA-mediated actions leads to an overall disinhibition within the neocortex ultimately resulting in epileptiform activity. The understanding of how the lack of NMDA receptors leads to the abnormal excitability in neurons could have potential clinical ramifications in that these results could provide insight for the development of better treatment for human epilepsy patients and interventions to prevent the development and occurrences of seizures.
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