The Role of Stress in a Genetically Predisposed Epilepsy Model

压力在遗传易感性癫痫模型中的作用

• 批准号: 8057544
• 负责人: NIKKI Tamara SAWYER
• 金额: $ 3.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057544
• 关键词: Acute; Adrenal Glands; Adult; Affect; Age-Years; Animals; Antiepileptic Agents; Area; Brain; Childhood; Chronic; Chronic stress; Clinical; Corticosterone; Corticotropin-Releasing Hormone; Development; Disease; Disease Progression; Electroencephalography; Environmental Risk Factor; Epilepsy; Exhibits; Exposure to; Family; Family member; Febrile Convulsions; Frequencies; Future; General Population; Generalized Epilepsy; Generations; Genes; Genetic; Genetic Predisposition to Disease; Goals; Heterogeneity; Hormones; Human; Inborn Genetic Diseases; Interneurons; Kindling (Neurology); Knock-in Mouse; Knowledge; Learning; Life Stress; Light; Limbic System; Longevity; Measures; Migraine; Modeling; Mus; Mutant Strains Mice; Mutation; Other Genetics; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Physiological; Plasma; Play; Population; Precipitating Factors; Predisposition; Reporting; Rodent; Role; Seizures; Severities; Shapes; Sodium Channel; Stress; System; Systems Development; Testing; Thymus Gland; Time; Weight; Work; acute stress; biological adaptation to stress; corticosterone receptor; hypothalamic-pituitary-adrenal axis; insight; mouse model; mutant; new therapeutic target; receptor expression; response; stressor; voltage

DESCRIPTION (provided by applicant): Epilepsy affects 1-2% of the population, and approximately 30% of epilepsy patients continue to suffer from seizures despite treatment with antiepileptic medications. Stress is the most common seizure precipitating factor reported by epilepsy patients, suggesting that the physiological stress response has the potential to be a new therapeutic target for the treatment of epilepsy. The majority of studies investigating the relationship between stress and epilepsy have used wildtype rodents with normal brain and stress system development. However, little is currently known about how a genetic predisposition to epilepsy interacts with the stress response to influence seizure outcome. Much is now being learned about genetic predispositions to epilepsy, and genetic factors are estimated to contribute to at least 40% of epilepsy cases. Patients with one epilepsy disorder in particular, genetic (generalized) epilepsy with febrile seizures plus (GEFS+), exhibit a wide range of seizure types and severities even within families sharing the same mutation. This clinical heterogeneity suggests that other environmental and/or genetic factors are playing a role in shaping seizure phenotype in GEFS+ patients. Our lab has developed a mouse model of GEFS+ created by knocking in a human SCN1A- GEFS+ mutation (R1648H) into the orthologous mouse gene (Scn1a). Heterozygous R1648H mice have a normal life span, exhibit infrequent spontaneous seizures, have a lower seizure threshold than their wildtype littermates, and have reduced excitability of cortical GABAergic inhibitory interneurons. This proposal will test the hypothesis that R1648H mutant mice will have altered basal stress system function, and that acute stress will increase seizure susceptibility, frequency, and severity of seizures in these mice. Aim 1 will examine the basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in the R1648H mutant mice by measuring plasma levels of corticosterone, a major stress hormone, in both the morning and evening. Corticosterone receptor expression and distribution within the brain will also be examined, particularly in areas that play a role in both the stress response and seizure generation. Adrenal and thymus gland weights will allow us to determine if the R1648H mutants have chronically altered systemic levels of corticosterone. Aim 2 will examine the response of these mice to an acute stressor. We will measure the corticosterone response to an acute stressor and determine the amount of time for levels to return to normal. We will use EEG analysis to determine if exposure to an acute stressor is sufficient to increase the frequency of spontaneous seizures. We will also test the effect on seizure threshold and seizure severity by using chemiconvulsants to induce seizures following acute stress exposure. The results from this study will provide new insight into the relationship between sodium channel function, stress, and epilepsy. The long-term objective of this project is to elucidate the mechanisms by which stress works to affect seizure outcome in a genetically predisposed model of epilepsy with the goal of identifying potential new targets for seizure control in epilepsy patients. PUBLIC HEALTH RELEVANCE: Epilepsy affects 1-2% of the general population, and approximately 30% of epilepsy patients do not respond to current treatments. Stress is the number one trigger for seizures reported by epilepsy patients. This proposal aims to investigate the relationship between a genetic predisposition to epilepsy and the stress response, with the goal of identifying new therapeutic targets for the treatment of epilepsy.

描述（由申请人提供）：癫痫会影响1-2％的人口，尽管接受抗癫痫药物治疗，但大约30％的癫痫患者仍继续癫痫发作。压力是癫痫患者报告的最常见的癫痫发作沉淀因子，这表明生理压力反应有可能成为治疗癫痫的新治疗靶点。研究压力与癫痫之间关系的大多数研究都使用了具有正常大脑和压力系统发育的野生型啮齿动物。然而，目前，关于癫痫的遗传易感性与影响癫痫结局的压力反应相互作用的知之甚少。现在，关于癫痫的遗传易感性，现在已经了解了很多，遗传因素估计有助于至少40％的癫痫病例。特别是患有一种癫痫疾病的患者，具有发热性癫痫发作（GEFS+）的遗传（广义）癫痫患者，甚至在共享相同突变的家庭中也表现出广泛的癫痫发作类型和严重性。这种临床异质性表明，其他环境和/或遗传因素在塑造GEFS+患者的癫痫发作表型中起作用。我们的实验室已经开发了一种通过将人类SCN1A-GEFS+突变（R1648H）敲打到直系同源小鼠基因（SCN1A）中而创建的GEFS+的小鼠模型。杂合R1648H小鼠的寿命正常，表现出很少自发性癫痫发作，癫痫发作阈值低于其野生型同窝仔，并降低了皮质GABA能抑制性抑制性中间神经元的兴奋性。该建议将检验以下假设：R1648H突变小鼠将改变基础应力系统功能，并且急性应力会增加这些小鼠癫痫发作的癫痫敏感性，频率和严重程度。 AIM 1将通过测量早晨和晚上的血浆（一种主要的应激激素）血浆水平（一种主要的应激激素）来检查R1648H突变小鼠R1648H突变小鼠中下丘脑 - 垂体 - 肾上腺（HPA）轴的基础活性。还将检查大脑内皮质酮受体的表达和分布，尤其是在压力反应和癫痫发作的领域。肾上腺和胸腺的重量将使我们能够确定R1648H突变体是否长期改变了全身性皮质酮水平。 AIM 2将检查这些小鼠对急性应激源的反应。我们将测量对急性应激源的皮质酮反应，并确定水平恢复正常的时间。我们将使用脑电图分析来确定暴露于急性应激源是否足以增加自发癫痫发作的频率。我们还将通过使用化学弹飞剂在急性应激暴露后诱导癫痫发作来测试对癫痫发作阈值和癫痫发作严重程度的影响。这项研究的结果将为钠通道功能，压力和癫痫之间的关系提供新的见解。该项目的长期目的是阐明压力在遗传易感模型中影响癫痫发作结果的机制，目的是确定癫痫患者癫痫发作控制的潜在新目标。 公共卫生相关性：癫痫影响1-2％的普通人群，大约30％的癫痫患者对当前治疗没有反应。压力是癫痫患者报告的癫痫发作的第一触发因素。该提案旨在研究遗传易癫痫的遗传易感性与压力反应之间的关系，目的是确定用于治疗癫痫的新治疗靶标。