Inhibitory single neuron control of human epilepsy

描述(申请人提供)：癫痫是一种经常使人虚弱的神经疾病，影响着300万美国人和全球5000多万人。尽管几十年来出色的临床、遗传学和基础研究，以及数十种动物模型和假说的存在，但人类局灶性癫痫的发病机制仍不清楚。要实现癫痫研究的“无发作，无副作用”的目标，首先需要回答一组基本问题：局灶性发作是如何开始的，如何扩散，如何终止？特别是，不同的神经元亚群--抑制性和兴奋性--在人类癫痫发作的进程中扮演着什么角色？顽固性癫痫患者的脑皮层脑电(ECoG)记录被用来定位癫痫发作的脑区。ECOG信号代表了数千个神经元的活动总和，并揭示了癫痫发作的许多重要的宏观特征。然而，许多来自癫痫动物模型的机制预测是在单个神经元的水平上进行的，不能仅使用ECoG进行测试。在这里，专门设计的记录技术和设备被用来安全地记录数百个神经元在癫痫发作期间的同时活动，这些神经元直接在药物耐药局灶性癫痫患者中发作。然后，我就有可能有选择地识别人类抑制神经元，并询问它们是如何控制癫痫发作的。许多动物和切片研究表明，抑制作用减弱会导致癫痫发作。然而，许多其他人表示，在癫痫发作发生之前，有必要增加抑制以同步活动。来自人类的这些抑制性中间神经元的直接记录为解决这一争论提供了一个独特的机会。通过仔细识别人类抑制性中间神经元，可以表征它们在人类癫痫发作的所有阶段的行为。然后，可以将这些人类抑制性中间神经元的活动与不同种类的兴奋细胞的活动进行比较。然后，抑制神经元的活动也可以在癫痫小鼠模型中进行光遗传操作，以证实人类观察到的将抑制神经元活动和癫痫发作强度联系起来的是因果关系，而不仅仅是相关的。这可以将该领域引向专门针对特定目标的癫痫的新的药理学、外科和预测性疗法。 神经元亚型。

DESCRIPTION (provided by applicant): Epilepsy is an often debilitating neurological condition affecting 3 million Americans and more than 50 million people across the globe. Despite several decades of excellent clinical, genetic and basic research and the existence of dozens of animal models and hypotheses, the mechanisms underlying human focal epilepsy are still not understood. To achieve the "no seizures, no side effects" goal of epilepsy research, we need to first answer a set of fundamental questions: how do focal seizures start, how do they spread, and how do they terminate? In particular, what roles do different subsets of neurons - inhibitory vs excitatory - play in the progression of human seizures? Intracranial electrocorticogram (ECoG) recordings in patients with intractable epilepsy are used to localize the brain region where seizures originate. ECoG signals represent the summed activity of thousands of neurons, and have revealed many important macroscopic features of seizures. However, many of the mechanistic predictions arising from animal models of epilepsy are at the level of individual neurons, and cannot be tested using ECoG alone. Here, specially designed recording techniques and devices are used to safely record the simultaneous activity of hundreds of individual neurons during seizures directly in patients with pharmacoresistant focal epilepsy. It i then possible to selectively identify human inhibitory neurons and ask how they control seizures. Many animal and slice studies state that decreased inhibition leads to seizures. However, many others state that increased inhibition is necessary to synchronize activity before a seizure can occur. Direct recordings of these inhibitory interneurons from humans present a unique opportunity to resolve this debate. By carefully identifying human inhibitory interneurons it is possible to characterize how they behave during all phases of human seizures. The activity of these human inhibitory interneurons can then be compared to that of different kinds of excitatory cells. The activity of inihibitory neurons can then also be manipulated optogenetically in mouse models of epilepsy to confirm that the human observations linking inhibitory neuron activity and seizure intensity are causal, and not just correlative. This can point the field towards novel pharmacological, surgical and predictive therapies for epilepsy that specifically target particular neuronal subtypes.