Regulation of pro-convulsive circuitry by kainate receptors.

描述（由申请人提供）：癫痫是一种广泛的神经系统疾病，影响世界人口的1-4%。虽然许多抗癫痫药物（AED）是可用的，但大约25%的病例无反应，包括与颞叶硬化和皮质畸形（CM）相关的病例。因此，非常需要更多的研究，重点是这些形式的癫痫发作的原因和潜在的治疗策略。在颞叶硬化症和CM相关癫痫中，据报道异常的促惊厥回路发生在海马结构的齿状回中，并被认为有助于癫痫发作的产生。然而，我们不明白的是，为什么癫痫发作只是偶尔发生在这些类型的癫痫，但异常的促惊厥回路是一个永久性的特征。这项研究项目将集中在确定是否存在异常红藻氨酸受体在这些异常的促惊厥电路的基础上，他们的能力，以产生零星的癫痫发作。在这项研究中，生物化学，解剖学和电生理学技术和两种癫痫模型的组合将被用来表征在促惊厥回路中发现的红藻氨酸受体，并确定是否在重复刺激过程中阻断或脱敏它们抑制癫痫发作。如果癫痫发作可以被抑制，并且这些红藻氨酸受体的特征被鉴定，则可以设计新的AED，其特异性靶向异常促惊厥回路中的红藻氨酸受体，从而抑制患有这些类型癫痫的患者的癫痫发作。公共卫生相关性：癫痫影响世界上大约1-4%的人口，其中高达25%的病例对目前可用的抗癫痫药物无反应。基于初步的数据，本研究计划提出调查是否异常红藻氨酸受体有助于颞叶硬化和皮质畸形相关癫痫模型的癫痫组织中癫痫发作的产生。这是一个关于发作的新假设，应该为治疗难治性癫痫提供新的治疗策略。

DESCRIPTION (provided by applicant): Epilepsy is a widespread neurological disorder that affects 1-4% of the world's population. While many anti-epileptic drugs (AEDs) are available, approximately 25% of cases are non-responsive including cases associated with temporal lobe sclerosis and cortical malformations (CM). Thus, there is a tremendous need for additional research that focuses on the cause of seizure generation in these forms of epilepsy and potential therapeutic strategies. In both temporal lobe sclerosis and CM-related epilepsy, abnormal pro-convulsive circuits have been reported to occur in the dentate gyrus of the hippocampal formation and have been suggested to contribute to the generation of seizures. What we do not understand however, is why seizures occur only sporadically in these types of epilepsy, yet the aberrant pro-convulsive circuits are a permanent feature. This research project will focus on determining whether the presence of aberrant kainate receptors in these abnormal pro-convulsive circuits underlie their capacity to generate seizures sporadically. In this study, a combination of biochemical, anatomical and electrophysiological techniques and two models of epilepsy will be used to characterize the kainate receptors found in pro-convulsive circuits and to determine whether blocking or desensitizing them suppresses seizure generation during repetitive stimulation. If seizure generation can be suppressed, and the characteristics of these kainate receptors identified, new AEDs can be designed that specifically target kainate receptors in aberrant pro-convulsive circuits and thereby suppress seizure generation in patients afflicted with these types of epilepsy. PUBLIC HEALTH RELEVANCE: Epilepsy affects approximately 1-4% of the world's population with up to 25% of cases being unresponsive to currently available anti-epileptic drugs. Based on preliminary data this research project proposes to investigate whether aberrant kainate receptors contribute to the generation of seizures in epileptic tissue from models of temporal lobe sclerosis and cortical malformation-related epilepsy. This is a novel hypothesis regarding ictogenesis that should provide insight into a new therapeutic strategy for treating medically-intractable epilepsy.