Role of dentate granule cell glucocorticoid receptors in neuronal excitability and status epilepticus

齿状颗粒细胞糖皮质激素受体在神经元兴奋性和癫痫持续状态中的作用

• 批准号: 10395954
• 负责人: Kimberly Lynn Kraus
• 金额: $ 3.99万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395954
• 关键词: Ablation; Action Potentials; Anticonvulsants; Anxiety; Benchmarking; Benzodiazepines; Bilateral; Brain; Brain Injuries; Brain region; Career Choice; Cell Death; Chronic; Clinical; Corticosterone; Development; Electrocorticogram; Epilepsy; Epileptogenesis; Failure; Feedback; Female; Foundations; Frequencies; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Goals; Hippocampus (Brain); Hormones; Hour; In Vitro; Injections; Injury; Intervention; Knock-out; Left; Life; Measures; Mediating; Medical emergency; Membrane; Mental Depression; Mentors; Morbidity - disease rate; Mus; National Institute of Neurological Disorders and Stroke; Neurology; Neurons; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Physicians; Pilocarpine; Play; Positioning Attribute; Property; Recurrence; Refractory; Research; Research Proposals; Rodent; Role; Scientist; Seizures; Serum; Severities; Severity of illness; Status Epilepticus; Stress; Survivors; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Training; Transgenic Mice; Translational Research; Viral; biological adaptation to stress; brain cell; brain circuitry; calmodulin-dependent protein kinase II; cell type; design; doctoral student; excitotoxicity; experience; granule cell; hypothalamic-pituitary-adrenal axis; improved; innovation; male; mortality; mouse model; neuronal excitability; novel strategies; patch clamp; prevent; psychiatric comorbidity; receptor expression; spatiotemporal; stressor; treatment strategy

PROJECT SUMMARY/ABSTRACT Patients in status epilepticus present with continuous seizures that are life-threatening without successful and emergent seizure termination. Despite the fact that current therapies fail to stop seizures in 20% of patients, physicians have relied on essentially the same treatment strategy for SE for almost 50 years: anti-seizure drugs, such as benzodiazepines and other anti-convulsive agents. When treatment fails, patients enter refractory SE for which the mortality rate can reach 60%. Not only is SE a medical emergency with a high mortality rate, survivors are often left with irreversible and lasting brain damage. After a single episode of SE, almost half of patients will develop spontaneous recurrent seizures and temporal lobe epilepsy. Further, psychiatric comorbidities, such as anxiety and depression, are highly associated with the chronic epileptic state. Therefore, to reduce both mortality and morbidity, it is imperative to elucidate the underlying mechanisms that drive the severity and consequences of SE. As a life-threatening stressor, SE results in robust activation of the hypothalamic-pituitary-adrenal axis and stress hormone (i.e., glucocorticoid) release. Multiple lines of evidence suggest that glucocorticoids can increase neuronal excitability under basal conditions and exacerbate excitotoxic injury under pathological conditions. In fact, we have shown that giving exogenous glucocorticoids to epileptic rodents makes seizures worse. However, exactly which brain regions or cell types mediate this effect is unknown. Here, I hypothesize that glucocorticoids worsen status epilepticus severity by increasing the excitability of hippocampal dentate granule cells. In the seizure-free brain, dentate granule cells limit or “gate” the amount of excitatory activity that can enter the hippocampus, thereby preventing the propagation of seizures. Dentate granule cells are rich in glucocorticoid receptor expression; therefore, if glucocorticoids increase dentate granule cell excitability, this gating function is likely to fail during SE, allowing seizures to grow and spread. To test my hypothesis, I have optimized a viral-mediated strategy to selectively delete glucocorticoid receptors from hippocampal dentate granule cells prior to pilocarpine-induced SE. Using this approach, I will determine whether glucocorticoid receptor deletion 1) decreases status epilepticus severity (Aim 1) and/or 2) decreases dentate granule cell excitability (Aim 2). These studies will reveal whether glucocorticoid receptor-mediated failure of the dentate gate plays a role in exacerbating status epilepticus-induced injury to the hippocampus.

项目总结/摘要 癫痫持续状态的患者表现为持续性癫痫发作，这些癫痫发作危及生命， 紧急终止癫痫发作。尽管目前的治疗方法不能阻止20%的患者癫痫发作， 近50年来，内科医生一直依赖于基本相同的SE治疗策略：抗癫痫药物， 例如苯二氮卓类和其它抗惊厥剂。当治疗失败时，患者进入难治性SE 死亡率可达60%。SE不仅是一种死亡率高的医疗紧急情况， 幸存者往往留下不可逆转和持久的脑损伤。在SE的一集之后，几乎一半的 患者会出现自发性反复发作和颞叶癫痫。此外，精神病 诸如焦虑和抑郁的合并症与慢性癫痫状态高度相关。因此，我们认为， 为了降低死亡率和发病率，有必要阐明驱动 SE的严重性和后果。 作为一种威胁生命的应激源，SE导致下丘脑-垂体-肾上腺轴的强烈激活和应激 激素（即，糖皮质激素）释放。多种证据表明，糖皮质激素可以增加 在基础条件下神经元兴奋性降低，在病理条件下加重兴奋性毒性损伤。在 事实上，我们已经证明，给予癫痫啮齿动物外源性糖皮质激素会使癫痫发作更严重。然而，在这方面， 究竟是哪些大脑区域或细胞类型介导了这种效应尚不清楚。在这里，我假设糖皮质激素 通过增加海马齿状回颗粒细胞的兴奋性来加重癫痫持续状态的严重程度。在 无脑区，齿状颗粒细胞限制或"门"的兴奋活动的数量，可以进入 海马，从而防止癫痫发作的传播。齿状颗粒细胞富含糖皮质激素 因此，如果糖皮质激素增加齿状颗粒细胞的兴奋性，这种门控功能是 可能在SE期间失败，允许癫痫发作增长和扩散。 为了验证我的假设，我优化了一种病毒介导的策略，选择性地删除糖皮质激素受体 从海马齿状回颗粒细胞的毛果芸香碱诱导的SE之前。使用这种方法，我将确定 糖皮质激素受体缺失是否1）降低癫痫持续状态的严重程度（目的1）和/或2）降低 齿状颗粒细胞兴奋性（Aim 2）。这些研究将揭示糖皮质激素受体介导的 齿状门的失效在加重癫痫持续状态引起的海马损伤中起作用。