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

项目摘要/摘要 处于癫痫持续状态的患者出现持续的癫痫发作，这些发作危及生命，但没有成功和 紧急终止癫痫发作。尽管目前的治疗方法未能阻止20%的患者癫痫发作， 近50年来，医生对SE基本上一直依赖相同的治疗策略：抗癫痫药物， 如苯二氮类药物和其他抗惊厥剂。当治疗失败时，患者进入难治性SE 死亡率可达60%。SE不仅是一个死亡率很高的紧急医疗事件， 幸存者往往会受到不可逆转的持久的脑损伤。在SE的一集之后，几乎一半的人 患者会出现自发性反复发作和颞叶癫痫。此外，精神病学 焦虑和抑郁等并存疾病与慢性癫痫状态高度相关。因此， 为了减少死亡率和发病率，有必要阐明推动 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 荷尔蒙(即糖皮质激素)释放。多条证据表明糖皮质激素可以增加 神经元在基础条件下的兴奋性，以及在病理条件下加剧兴奋性毒性损伤。在……里面 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加剧癫痫发作。然而， 目前尚不清楚具体是哪些脑区或细胞类型参与了这种效应的调节。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。在 无癫痫发作的大脑，齿状颗粒细胞限制或“门”的兴奋性活动量，可以进入 海马体，从而防止癫痫的传播。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 很可能在SE期间失败，允许癫痫发作增长和蔓延。 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 在匹罗卡品诱发SE前的海马齿状颗粒细胞中。使用这种方法，我将确定 糖皮质激素受体缺失1)是否降低癫痫持续状态的严重程度(目标1)和/或2 齿状颗粒细胞兴奋性(目标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对海马区的损伤中起着重要作用。

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.