Sex differences in SUDEP susceptibility: the role of progesterone and estradiol

项目摘要： 癫痫是世界范围内最常见的神经系统疾病之一。尽管有大量 在现有的抗癫痫药物（AED）中，超过三分之一的癫痫患者无法 用药物控制他们的癫痫发作，使他们处于更高的突然意外死亡的风险中， 癫痫（SUDEP）。SUDEP是耐药性癫痫患者死亡的主要原因， 虽然它分布在所有年龄段，影响男性和女性，但它在 男性。在一些女性癫痫患者中，癫痫发作的频率和严重程度是波动的， 与性类固醇水平的变化相对应可能性类固醇在调节 癫痫发作，并可能解释SUDEP发病率的性别差异。 为了评估性类固醇在癫痫发作和SUDEP易感性中的作用，我们使用了急性和慢性的 在Dravet综合征（DS）的小鼠模型中用孕酮和雌二醇（P+E）治疗， Scn 1aR 1407 X/+功能丧失突变。我们的初步数据表明， P+E急性处理的雌性和雄性小鼠的癫痫发作表型均得到改善。缺陷 5-羟色胺（5-HT）系统和GABA能功能缺陷与癫痫发作有关， SUDEP。动物研究表明，P+E急性和慢性治疗可增加5-HT 增加脑内GABA浓度，并增加海马体中的紧张性GABA抑制。其次，性 已知类固醇刺激呼吸，潜在地提供了一种方法来拯救呼吸系统疾病。 在DS小鼠中观察到表型。因此，我们将检验以下工作假设：1）P+E下降 通过降低癫痫发作频率和/或严重程度以及刺激呼吸来降低SUDEP发生率，以及2） P+E的抗惊厥作用由5-羟色胺和/或GABA介导。慢性和 将通过视频评估急性P+E治疗对癫痫发作、SUDEP发生率和呼吸的影响- 自发性和高血压诱发癫痫发作的EEG/EKG监测。使用DS小鼠，其中5- HT神经元已被基因删除，我将确定是否血清素介导的 急性和慢性P+E治疗的抗惊厥作用。最后，我将评估 DS小鼠海马切片中GABA-A介导的紧张性抑制与野生型小鼠相比的差异 使用全细胞膜片钳技术，在急性应用和未急性应用P+E或其代谢产物的情况下 录音.这项工作将为性类固醇在SUDEP中的作用提供更清晰的见解。 发病率。此外，由于癫痫发作易感性的性别差异是癫痫中广泛关注的问题， 确定性类固醇如何影响多巴胺能和GABA能神经通路，可以提供 为男性和女性癫痫患者提供更有效的治疗策略。

Project Abstract: Epilepsy is one of the most common neurological diseases worldwide. Despite a large number of available antiepileptic drugs (AEDs), more than one-third of people with epilepsy are not able to control their seizures with medication, putting them at higher risk for sudden unexpected death in epilepsy (SUDEP). SUDEP is a major cause of death in patients with drug-resistant epilepsy, and while it is distributed across all ages and affects both males and females, it is more prevalent in males. In some epileptic females, seizure frequency and severity are known to fluctuate, corresponding to changes in sex steroid levels. Possibly, sex steroids play a role in the regulation of seizures and might account for the sex difference in SUDEP incidence. To evaluate the role of sex steroids in seizure and SUDEP susceptibility, we used acute and chronic treatment of progesterone and estradiol (P+E) in a mouse model of Dravet Syndrome (DS) with a Scn1aR1407X/+ loss-of-function mutation. Our preliminary data demonstrate that SUDEP incidence and the seizure phenotype are improved in female and male mice acutely treated with P+E. Defects in the serotonin (5-HT) system and deficits in GABAergic function are associated with seizures and SUDEP. Animal studies have shown that acute and chronic treatment with P+E can increase 5-HT concentration in the brain and increase tonic GABA inhibition in the hippocampus. Further, sex steroids are known to stimulate breathing, potentially providing a method to rescue the respiratory phenotype observed in DS mice. Thus, we will test the working hypotheses that 1) P+E decrease SUDEP incidence by reducing seizure frequency and/or severity, and stimulating breathing, and 2) the anticonvulsant effects of P+E are mediated by serotonin and/or GABA. The effect of chronic and acute P+E treatment on seizures, SUDEP incidence, and breathing will be assessed through video- EEG/EKG monitoring of spontaneous and hyperthermia-induced seizures. Using DS mice in which 5- HT neurons have been genetically deleted, I will determine whether serotonin mediates the anticonvulsant effects conferred by acute and chronic P+E treatment. Lastly, I will assess for differences in GABA-A mediated tonic inhibition in the hippocampal slice of DS mice compared to wild type with and without acute application of P+E, or their metabolites, using whole-cell patch-clamp recordings. The proposed work will provide clearer insight into the role of sex steroids in SUDEP incidence. Further, as sex differences in seizure susceptibility are a widespread concern in epilepsy, identifying how sex steroids impact the serotonergic and GABAergic neural pathways, could provide clinicians with more effective treatment strategies for both male and female epilepsy patients.