Regulation of pro-convulsive circuitry by kainate receptors.

描述(申请人提供)：癫痫是一种广泛存在的神经系统疾病，影响世界人口的1-4%。虽然有许多抗癫痫药物(AED)可用，但大约25%的病例是无反应的，包括与颞叶硬化和皮质畸形(CM)相关的病例。因此，极有必要进行更多的研究，重点研究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，已有报道在海马结构的齿状回出现异常的前惊厥回路，并被认为是导致癫痫发作的原因之一。然而，我们不明白的是，为什么癫痫发作只在这些类型的癫痫中零星发生，而异常的前惊厥回路是一个永久性的特征。这项研究项目将集中于确定这些异常的前惊厥回路中异常的红藻氨酸受体的存在是否支持它们产生零星发作的能力。在这项研究中，结合生化、解剖学和电生理学技术和两种癫痫模型，将被用来描述前癫痫回路中发现的红藻氨酸受体的特征，并确定阻断或脱敏它们是否能抑制重复刺激过程中癫痫的产生。如果能够抑制癫痫的产生，并确定这些海人酸受体的特征，就可以设计出新的抗癫痫药物，专门针对异常的前癫痫回路中的海人酸受体，从而抑制患有这些类型癫痫的患者的癫痫发生。公共卫生相关性：癫痫影响世界人口的大约1-4%，高达25%的病例对现有的抗癫痫药物无效。基于初步数据，该研究项目建议从颞叶硬化症和皮质畸形相关癫痫的模型中调查异常的海人酸受体是否有助于癫痫组织癫痫发作的发生。这是一个关于内生性癫痫发生的新假说，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.