Role of Neuronal Loss in Epileptogenesis

项目摘要 海马区的细胞丢失是颞叶癫痫(TLE)最一致的发现之一，还有两个 齿状回中的神经元群被认为可能是最容易受到损害的- 生长抑素GABA能神经元和苔藓细胞。虽然这些神经元在癫痫中经常被耗尽， 许多其他神经元也在海马区和其他脑区丢失，因此它保留了下来 很难在这些特殊神经元的丧失和随后的发育之间建立强有力的联系 癫痫发作的症状。随着新的转基因动物和消融特定群体的方法的发展 神经元，现在可以用工具来确定这两组神经元选择性丢失的影响 齿状门。这一提议的广泛假设是选择性地消融双侧肺门 生长抑素神经元和苔藓细胞会导致自发性癫痫的发生。这个 假说并不意味着这种细胞丢失模式是唯一或可能导致 TLE发展，但相反，两种细胞类型的综合损失足以发展 行为癫痫，并潜在地刺激相关的形态和功能变化。 特殊目标1将检验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。随着时间的推移，将监测心电和行为活动 同步的视频-脑电记录，以识别潜在的癫痫活动并确定行为 相互关联。特殊目标2将检验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测器将 可用于表征颗粒细胞活性和识别癫痫发展的早期迹象。具体目标3 将检验选择性肺门细胞丢失将导致海马区依赖行为改变的假设 任务。预测的齿状颗粒细胞活性的相关增加可能会损害 齿状回，以限制传入信息，这是在大脑中最佳信息处理所必需的 海马体。环境辨别和类似焦虑的活动的测试将被用来识别行为 选择性肺门神经元丢失的影响。特定目标4将检验选择性肺门细胞消融的假设 可作为剩余海马神经元轴突重组的刺激。神经解剖学 研究将被用来确定两组肺门神经元的丧失是否足以刺激 苔藓纤维和剩余的GABA神经元，从而复制了在人类中常见的变化 TLE。拟议中的研究可能提供第一个直接证据，证明特定肺门神经元群的丧失 可导致自发性癫痫的发展，直接或由于相关的变化 海马环路，可提供一种独特的海马局灶性(复杂部分)癫痫模型。

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.