Sodium channels and neuronal excitability in chronic limbic epilepsy.

癫痫是一种以反复自发性发作为特征的重要神经系统疾病。是 据估计，超过230万美国人患有癫痫症，其中20万例新的癫痫症被诊断出来 每年.癫痫是每年25，000至50，000名患者死亡的一个因素，估计 每年花费125亿美元。因此，癫痫是老年人的主要经济和个人负担。 美国公众不幸的是，抗癫痫药物（AED）在大约30%的患者中无效。太 通常治疗与不良副作用有关，这可能是AED影响其 在癫痫发作区以外的区域的目标。为了开发更有效的治疗方法， 有一个协调一致的努力，以了解神经元成为 在癫痫中过度兴奋。在慢性癫痫中，分子和细胞变化发生在癫痫发作期间 区域，使其能够产生自发性癫痫发作。很明显，这些变化有一个 改变药理学，使新的治疗方法，更具体的原因， 通过识别癫痫发作区特有的重要变化将极大地帮助癫痫。 在这个提议中，我们将研究钠（Na）通道在癫痫发生中的变化。na通道 在控制神经元兴奋性中起关键作用，因此Na通道阈值和放电的变化 模式对系统兴奋性有显著影响。钠通道行为的改变，作为 钠通道突变，已知是负责一些遗传形式的全身性癫痫。我们 中心假设是，改变钠通道的表达和生理，使神经元更多， 易兴奋广泛存在于边缘系统癫痫发作区。为了支持这一假设， 癫痫病的治疗方法有哪些？癫痫病的治疗方法有哪些？ 自发性癫痫发作，因此不是癫痫发作的后果。我们的建议将集中在 内侧内嗅皮层（mEC）和下托神经元，使用颞叶癫痫（TLE）动物模型， 一种常见的成人抗药性癫痫我们提供的初步数据表明， 在癫痫动物中，第II层神经元本质上是超兴奋的， 改变了我们发现，神经元兴奋性和Na通道行为的变化发生在神经元兴奋性出现之前。 自发性癫痫这些发现支持了我们的中心假设，即Na通道表达的变化 和生理学都有助于癫痫的发展。

Epilepsy is a significant neurological disorder characterized by recurrent spontaneous seizures. It is estimated that over 2.3 million Americans have epilepsy with 200,000 new cases of epilepsy being diagnosed each year. Epilepsy is a factor in the deaths of between 25,000 to 50,000 patients each year and is estimated to cost the US $12.5 billion each year. Epilepsy therefore, is a major economic and personal burden for the American public. Unfortunately, antiepileptic drugs (AEDs) are ineffective in approximately 30% of patients. Too often treatment is associated with adverse side effects which may be the result of the AEDs affecting their targets in regions outside the seizure onset zone. In order to develop more effective treatments with fewer side effects there has been a concerted effort to understand the underlying mechanisms by which neurons become hyperexcitable in epilepsy. In chronic epilepsy molecular and cellular changes occur within the seizure onset zone, making it capable of generating spontaneous seizures. It has become clear that these changes have an altered pharmacology so that the development of new therapies that are more specific for the causes of epilepsy will be greatly aided by identifying important changes that are unique to the seizure onset zone. In this proposal we will examine the changes in sodium (Na) channels in epileptogenesis. Na channels play a critical role in controlling neuronal excitability, and so changes in Na channel thresholds and firing patterns would have significant effects on system excitability. Alterations in Na channel behavior, as a result of Na channel mutations, are known to be responsible for a number of inherited forms of generalized epilepsy. Our central hypothesis is that alterations in the expression and physiology of Na channels that make neurons more excitable are found broadly in the limbic system seizure onset zone. To help support the hypothesis that these changes contribute to the development of epilepsy it is necessary to show that the changes occur before the onset of spontaneous seizures and are thus not a consequence of the seizures. Our proposal will focus on medial entorhinal cortex (mEC) and subiculum neurons using an animal model of temporal lobe epilepsy (TLE), a common form of adult pharmaco-resistant epilepsy. We provide preliminary data demonstrating that mEC layer II neurons are intrinsically hyperexcitable in epileptic animals and that Na channel physiology is also altered. We show that changes in neuronal excitability and Na channel behavior occur before the appearance of spontaneous seizures. These findings support our central hypothesis that changes in Na channel expression and physiology contribute to the development of epilepsy.