Role of Neuronal Loss in Epileptogenesis

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Project Summary Cell loss in the hippocampus is one of the most consistent findings in temporal lobe epilepsy (TLE), and two groups of neurons in the dentate gyrus have been identified as potentially the most vulnerable to damage – somatostatin GABAergic neurons and mossy cells. While these neurons are frequently depleted in epilepsy, numerous other neurons are also lost in the hippocampus and other brain regions, and thus it has remained difficult to establish a strong link between the loss of these particular neurons and the subsequent development of seizures. With the development of new transgenic animals and methods for ablating specific groups of neurons, tools are now available for determining the effects of selective loss of these two groups of neurons in the dentate hilus. The broad hypothesis of this proposal is that selective ablation of both hilar somatostatin neurons and mossy cells will lead to the development of spontaneous seizures. The hypothesis does not imply that this pattern of cell loss is the only or central change that could lead to the development of TLE but, instead, that combined loss of both cell types is sufficient for the development of behavioral seizures and potentially serves as a stimulus for related morphological and functional changes. Specific Aim 1 will test the hypothesis that selective ablation of the two groups of hilar neurons will lead to spontaneous seizures in these animals. Electrographic and behavioral activity will be monitored over time with synchronized video-EEG recordings to identify potential seizure activity and determine the behavioral correlates. Specific Aim 2 will test the hypothesis that selective ablation of these hilar neurons will lead to excessive activity of dentate gyrus granule cells in vivo. Silicon-based probes with microelectrode arrays will be used to characterize granule cell activity and identify early signs of seizure development. Specific Aim 3 will test the hypothesis that selective hilar cell loss will lead to alterations in hippocampal-dependent behavioral tasks. The predicted associated increases in dentate granule cell activity could compromise the ability of the dentate gyrus to limit incoming information, as is necessary for optimal information processing in the hippocampus. Tests of context discrimination and anxiety-like activity will be used to identify the behavioral effects of selective hilar neuron loss. Specific Aim 4 will test the hypothesis that selective hilar cell ablation can serve as a stimulus for axonal reorganization of remaining hippocampal neurons. Neuroanatomical studies will be used to determine if loss of two groups of hilar neurons is sufficient to stimulate sprouting of mossy fibers and remaining GABA neurons, thus replicating changes that are commonly observed in human TLE. The proposed studies could provide the first direct evidence that loss of specific groups of hilar neurons can lead to development of spontaneous seizures, either directly or as a result of related changes in hippocampal circuitry, and could provide a unique model of focal hippocampal (complex partial) seizures.