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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要癫痫持续状态患者会出现持续性癫痫发作，如果没有成功和有效的治疗，可能会危及生命。尽管目前的治疗无法阻止 20% 的患者癫痫发作，近 50 年来，医生一直依赖基本相同的 SE 治疗策略：抗癫痫药物、如苯二氮卓类药物和其他抗惊厥药物治疗失败时，患者会进入难治性 SE。 SE不仅是一种死亡率很高的医疗紧急情况，几乎一半的幸存者在一次 SE 发作后往往会留下不可逆转的持久脑损伤。患者会出现自发性反复发作和颞叶癫痫。因此，焦虑和抑郁等合并症与慢性癫痫状态高度相关。为了降低死亡率和发病率，必须阐明驱动这一现象的根本机制。 SE 的严重性和后果。作为一种危及生命的压力源，SE 会导致下丘脑-垂体-肾上腺轴的强烈激活和压力多种证据表明糖皮质激素可以增加激素（即糖皮质激素）的释放。基础条件下的神经元兴奋性和病理条件下的兴奋性毒性损伤恶化。事实上，我们已经证明，给癫痫啮齿动物服用外源性糖皮质激素会使癫痫发作更加严重。到底是哪些大脑区域或细胞类型介导了这种作用尚不清楚，在这里，我勇敢地说糖皮质激素。通过增加海马齿状颗粒细胞的兴奋性来恶化癫痫持续状态的严重程度。在无癫痫发作的大脑中，齿状颗粒细胞限制或“控制”可以进入大脑的兴奋性活动量。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。受体表达；因此，如果糖皮质激素增加齿状颗粒细胞的兴奋性，则该门控功能是 SE 期间可能会失败，导致癫痫发作增长和扩散。为了验证我的假设，我优化了病毒介导的策略来选择性删除糖皮质激素受体使用这种方法，我将确定毛果芸香碱诱导 SE 之前的海马齿状颗粒细胞。糖皮质激素受体缺失 1) 是否会降低癫痫持续状态的严重程度（目标 1）和/或 2）这些研究将揭示糖皮质激素受体是否介导齿状颗粒细胞的兴奋性。齿状门的故障会加剧癫痫持续状态引起的海马损伤。