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严重神经系统疾病。它是 据估计，超过230万美国人患有癫痫，新增癫痫病例20万例 每年。癫痫是每年导致25,000至50,000名患者死亡的一个因素，据估计 每年花费美国125亿美元。因此，癫痫是一项重大的经济和个人负担 美国公众。不幸的是，抗癫痫药物(AEDs)对大约30%的患者无效。太 治疗往往伴随着不良反应，这可能是由于AEDs影响了他们的 癫痫发作起始区以外区域的目标。为了用更少的副作用开发更有效的治疗方法 人们一直在共同努力，以了解神经元形成的潜在机制 癫痫时易激动的。在慢性癫痫中，分子和细胞的变化发生在癫痫发作期间。 区域，使其能够产生自发癫痫发作。很明显，这些变化有一个 改变了药理学，从而开发出更具针对性的新疗法 通过识别癫痫发作区域独有的重要变化，癫痫将得到极大的帮助。 在这项建议中，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方面起着关键作用，因此钠通道阈值和放电的变化 模式会对系统的兴奋性产生重大影响。钠通道行为的改变，作为结果 NA通道突变，已知是导致一些遗传性全身性癫痫的原因。我们的 中心假说是钠通道的表达和生理变化使神经元 易兴奋的广泛存在于边缘系统癫痫发作的起始区。帮助支持这样的假设，即这些 变化有助于癫痫的发展，有必要表明变化发生在 自发性癫痫发作，因此不是癫痫发作的后果。我们的提案将重点放在 使用颞叶癫痫(TLE)动物模型的内侧内嗅皮层(MEC)和下丘脑神经元， 一种常见的成人耐药癫痫。我们提供的初步数据表明，MEC 癫痫动物的第二层神经元本质上是高度兴奋的，钠通道生理学也是如此 被更改了。我们发现神经元兴奋性和钠通道行为的改变发生在 自发性癫痫。这些发现支持我们的中心假设，即钠通道表达的变化 而生理因素对癫痫的发展也有贡献。

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.