Role of Neuronal Loss in Epileptogenesis

项目摘要 海马中的细胞丢失是颞叶癫痫（TLE）中最一致的发现之一， 齿状回中的神经元群被认为是最容易受到损伤的神经元群， 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， 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丢失和随后的发育之间建立强有力的联系。 癫痫发作随着新的转基因动物和用于切除特定的细胞群的方法的发展， 神经元，工具现在可用于确定这两组神经元的选择性损失的影响， 齿状门该建议的广泛假设是，选择性消融两个肺门， 生长抑素神经元和苔藓细胞将导致自发性癫痫发作的发展。的 这一假设并不意味着这种细胞丢失模式是唯一或中心的变化，可能导致 但是，相反，两种细胞类型的联合损失足以发展TLE。 行为癫痫发作，并可能作为相关的形态和功能变化的刺激。 具体目标1将检验选择性消融两组肺门神经元将导致 自发性癫痫发作电图和行为活动将随着时间的推移进行监测， 同步视频脑电图记录，以识别潜在的癫痫发作活动，并确定行为 相互关联具体目标2将检验选择性消融这些门神经元将导致 在体齿状回颗粒细胞过度活动。具有微电极阵列的硅基探针将 用于表征颗粒细胞活性和识别癫痫发作发展的早期迹象。具体目标3 将检验选择性肺门细胞丢失将导致依赖于海马的行为改变的假设。 任务预测的齿状颗粒细胞活性的相关增加可能会损害细胞的能力。 齿状回，以限制传入的信息，这是必要的最佳信息处理中， 海马体。上下文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 可以作为剩余海马神经元轴突重组的刺激。神经解剖 研究将用于确定两组门神经元的损失是否足以刺激神经元的发芽。 苔藓纤维和剩余的GABA神经元，从而复制人类常见的变化 TLE。这项研究提供了第一个直接的证据，表明特定的肺门神经元群的缺失 可导致自发性癫痫发作的发展，无论是直接或作为相关变化的结果， 海马电路，并可以提供一个独特的模型局灶性海马（复杂部分）癫痫发作。

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.