Differential roles of neuronal and astrocytic aromatase in status epilepticus and chronic epilepsy

神经元和星形细胞芳香酶在癫痫持续状态和慢性癫痫中的不同作用

• 批准号: 10350333
• 负责人: Catherine A Christian-Hinman
• 金额: $ 43.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350333
• 关键词: Address; Affect; Amygdaloid structure; Area; Aromatase; Aromatase Inhibition; Astrocytes; Attention; Benchmarking; Biochemical; Brain; Brain region; Breeding; Cells; Chronic; Cognition; Cre-LoxP; Data; Development; Electrodes; Electroencephalography; Enzymes; Epilepsy; Epileptogenesis; Estradiol; Estrogen Receptors; Estrogens; Female; Genetic Recombination; Goals; Hilar; Hippocampus (Brain); Histologic; Histology; Hour; Human; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Injections; Injury; Ipsilateral; Ischemia; Kainic Acid; Knowledge; Light; Link; LoxP-flanked allele; Measurement; Memory; Menstrual cycle; Monitor; Mus; National Institute of Neurological Disorders and Stroke; Neurologic; Neurons; Ovarian; Ovary; Pattern; Pharmacology; Pharmacotherapy; Phase; Predisposition; Production; Property; Rattus; Recurrence; Research; Role; Saline; Seizures; Severities; Source; Status Epilepticus; Stroke; Tamoxifen; Temporal Lobe Epilepsy; Testing; Testosterone; Transgenic Mice; Trauma; Woman; cell type; dentate gyrus; granule cell; hippocampal sclerosis; implantation; improved; insight; knock-down; male; mouse model; novel; novel therapeutic intervention; prevent; relating to nervous system; selective expression; sex; side effect; synaptic function; translational impact

PROJECT SUMMARY A relationship between estrogens and epilepsy has long been acknowledged with estrogens, such as estradiol, primarily linked to proconvulsant effects. The ovaries traditionally receive the most attention as sources of estradiol, particularly in the context of catamenial seizure exacerbations in association with certain estradiol- dominant phases of the menstrual cycle in women. However, the brain itself is a source of estradiol in both sexes. Estradiol is synthesized from testosterone by the aromatase enzyme, which is highly expressed in the brain, particularly in areas strongly implicated in epilepsy. In the hippocampus, aromatase is almost exclusively expressed in neurons in basal conditions, but after trauma such as injury or stroke, astrocytes can also show high levels of aromatase expression. Roles for brain-derived estradiol in epilepsy, and the specific roles of neurons and astrocytes as sources of estradiol in this relationship, remain unclear. The proposed research will address major gaps in knowledge regarding the relative contributions of aromatase and estrogen synthesis in neurons vs. astrocytes in relation to two distinct states of seizure activity: status epilepticus (SE) and chronic epilepsy, the state of spontaneous recurrent seizures. Our rationale is that understanding distinct roles of neurons and astrocytes as sources of estrogens at different phases of SE and epilepsy will enable development of new therapeutic strategies to selectively target production of brain-derived estrogens and maximize seizure- suppressive effects, while minimizing deleterious effects on synaptic function and memory. We will use a novel combination of transgenic mice and controlled cell-specific reduction of aromatase, in combination with 24-hour video-EEG monitoring of seizures, multilabel immunofluorescence microscopy, and biochemical measurement of hippocampal estradiol to test our overall hypothesis that neurons and astrocytes have differential roles as sources of hippocampal estradiol in SE and chronic epilepsy. In Aim 1, we will define the temporal dynamics of hippocampal neuronal and astrocytic aromatase expression in association with SE, epileptogenesis, and chronic epilepsy. In Aims 2 and 3, we will determine the roles of hippocampal neuronal vs. astrocytic aromatase in SE susceptibility and chronic epilepsy, respectively. These studies will use a mouse model of epilepsy that recapitulates several critical EEG and histopathological features of human temporal lobe epilepsy. These studies will have positive translational impact by providing new insights into the dynamics of aromatase expression in neurons and astrocytes in SE and chronic epilepsy, and thereby address multiple goals of the 2020 NINDS Epilepsy Research Benchmarks to understand causes of epilepsy and related neurologic conditions, to prevent the progression of epilepsy, and improve treatment options while minimizing side effects.

项目摘要 长期以来，雌激素（例如雌二醇），雌激素与癫痫之间的关系已经认可 主要与突发效应有关。传统上，卵巢作为来源的最大关注 雌二醇，尤其是在可见性癫痫发作的情况下与某些雌二醇相关的 女性月经周期的主要阶段。但是，大脑本身都是雌二醇的来源 性别。雌二醇是由芳香酶从睾丸激素合成的，芳香化酶在高度表达 大脑，尤其是在癫痫与癫痫的强烈区域。在海马中，芳香酶几乎完全是 在基础条件下在神经元中表达，但是在损伤或中风等创伤之后，星形胶质细胞也可以显示 高水平的芳香酶表达。大脑衍生雌二醇在癫痫中的作用，以及 在这种关系中，神经元和星形胶质细胞作为雌二醇的来源，尚不清楚。拟议的研究将 解决有关芳香酶和雌激素合成在相对贡献中的知识中的主要差距 神经元与星形胶质细胞相对于两个不同的癫痫活性状态：状态癫痫症（SE）和慢性 癫痫病，自发癫痫发作的状态。我们的理由是了解 神经元和星形胶质细胞作为SE和癫痫不同阶段的雌激素来源 新的治疗策略，以选择性地靶向脑衍生的雌激素的产生并最大化癫痫发作 抑制作用，同时最大程度地减少对突触功能和记忆的有害影响。我们将使用小说 转基因小鼠和受控细胞特异性芳香酶的结合，结合24小时 视频EEG监测癫痫发作，多标签免疫荧光显微镜和生化测量 海马雌二醇的总体假设，即神经元和星形胶质细胞具有不同的作用 SE和慢性癫痫中海马雌二醇的来源。在AIM 1中，我们将定义的时间动态 海马神经元和星形细胞芳香酶表达与SE，癫痫发生和慢性 癫痫。在目标2和3中，我们将确定海马神经元与星形胶质细胞芳香酶在SE中的作用 敏感性和慢性癫痫。这些研究将使用癫痫的小鼠模型 概括了人类颞叶癫痫的几个关键脑电图和组织病理学特征。这些研究 通过提供对芳香化酶表达动力学的新见解，将产生积极的翻译影响 SE和慢性癫痫中的神经元和星形胶质细胞，从而解决2020 Ninds的多个目标 癫痫研究基准，以了解癫痫病和相关神经系统疾病的原因，以防止 癫痫的进展，改善治疗选择，同时最大程度地减少副作用。