Role of Neuronal Loss in Epileptogenesis

项目概要 海马细胞丢失是颞叶癫痫 (TLE) 最一致的发现之一，并且两个 齿状回中的神经元群已被确定为可能最容易受到损伤的—— 生长抑素 GABA 能神经元和苔藓细胞。虽然这些神经元在癫痫症中经常被耗尽， 海马体和其他大脑区域的许多其他神经元也丢失了，因此它仍然存在 很难在这些特定神经元的丧失和随后的发育之间建立牢固的联系 癫痫发作。随着新的转基因动物和消除特定群体的方法的发展 神经元，现在可以使用工具来确定这两组神经元选择性丢失的影响 齿状门。该提案的广泛假设是选择性消融两个肺门 生长抑素神经元和苔藓细胞会导致自发性癫痫发作的发展。的 假设并不意味着这种细胞损失模式是可能导致 TLE 的发展，但相反，两种细胞类型的联合损失足以发展 行为癫痫发作并可能作为相关形态和功能变化的刺激。 具体目标 1 将检验以下假设：选择性消融两组肺门神经元将导致 这些动物的自发性癫痫发作。随着时间的推移，将监测电图和行为活动 同步视频脑电图记录，以识别潜在的癫痫活动并确定行为 相关。具体目标 2 将检验以下假设：选择性消融这些肺门神经元将导致 体内齿状回颗粒细胞过度活跃。带有微电极阵列的硅基探针将 用于表征颗粒细胞活性并识别癫痫发作的早期迹象。具体目标 3 将检验选择性肺门细胞损失将导致海马依赖性行为改变的假设 任务。齿状颗粒细胞活性的预测相关增加可能会损害 齿状回限制传入信息，这是最佳信息处理所必需的 海马体。情境辨别和焦虑样活动的测试将用于识别行为 选择性肺门神经元丢失的影响。具体目标 4 将检验选择性肺门细胞消融的假设 可以作为剩余海马神经元轴突重组的刺激物。神经解剖学 研究将用于确定两组肺门神经元的损失是否足以刺激 苔藓纤维和剩余的 GABA 神经元，从而复制在人类中常见的变化 TLE。拟议的研究可以提供第一个直接证据，证明特定群体的肺门神经元的丧失 可直接或由于相关变化而导致自发性癫痫发作 海马回路，并且可以提供局灶性海马（复杂部分）癫痫发作的独特模型。

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.