Targeted interneuron ablation and epileptogenesis

描述(申请人提供)：GABA能中间神经元的丢失是颞叶癫痫的一个主要特征，在人类患者和动物模型中都是如此。这项拟议研究的目的是确定选择性、局灶性中间神经元损害是否会导致发作间歇期。 尖峰和癫痫发作。这项研究将检验这一假说，即神经元间丢失独立于其他局部电路机制，对癫痫发作的产生有重要贡献。拟议的研究将利用神经毒素方法以及独立的遗传技术，选择性地消融中间神经元。这两种方法最初将损害不同种类的中间神经元，但随后的研究将集中在中间神经元的特定亚型上。在神经元间消融之后，将进行连续的在体视频-LFP监测和对剩余的主细胞及其网络的电生理特性进行体外评估。这些实验结果将加深我们对GABA能中间神经元丢失在癫痫发生和癫痫发生中所起作用的理解。 公共卫生相关性：在颞叶癫痫中，人们容易癫痫发作，这扰乱了他们的日常生活。这种疾病通过改变大脑不同部位的沟通方式影响着数百万人。这项研究将阐明导致这种疾病的生物学机制。具体地说，我们将研究选择性地从大脑中移除一小部分“抑制性”神经细胞如何有助于癫痫大脑中癫痫发作的产生。

DESCRIPTION (provided by applicant): Loss of GABAergic interneurons is a major feature of temporal lobe epilepsy, both in human patients as well as animal models. The aim of the proposed research is to determine whether selective, focal interneuron lesions result in interictal spikes and seizures. This research will test the hypothesis that interneuron loss, independent of other local-circuit mechanisms, contributes significantly to the generation of epileptic seizures. The proposed studies will utilize a neurotoxin approach, as well as an independent genetic technique, to selectively ablate interneurons. The two approaches will initially lesion heterogeneous populations of interneurons, but subsequent studies will focus on specific sub-types of interneurons. The interneuron ablations will be followed by continuous in vivo video-LFP monitoring and in vitro assessment of the electrophysiological properties of the remaining principal cells and their networks. The results of these experiments will improve our understanding of the role that the loss of GABAergic interneurons plays in seizure generation and epileptogenesis. PUBLIC HEALTH RELEVANCE: In temporal lobe epilepsy, people become susceptible to seizures, which disrupt their daily lives. This disease affects millions of people by changing the way different parts of their brain communicate. This research will shed light onto the biological mechanisms that lead to this disease. Specifically, we will study how selective removal of a small sub-population of "inhibitory" nerve cells from the brain contributes to the generation of seizures in the epileptic brain.