Roles of neuroestradiol in comorbid hyperexcitability and seizure susceptibility in Alzheimer Disease

项目摘要 阿尔茨海默病（AD）患者癫痫发作的风险增加。女性的AD发病率高于 在绝经期和绝经后， 被认为是AD认知和记忆缺陷的一个因素。然而，雌二醇主要与癫痫发作有关 对癫痫有促进作用。因此，雌二醇可能具有支持认知功能的有益效果， 在AD与共病癫痫发作中的有害（促惊厥）作用。雌二醇是由睾酮合成的， 芳香酶与AD和癫痫高度相关的大脑区域，如海马 和皮质，在雄性和雌性中表达高水平的芳香化酶。先前的研究表明， 芳香化酶抑制剂抑制癫痫发作的易感性，但这种作用尚未在 AD.因此，关于脑源性雌二醇（神经雌二醇）的作用， 兴奋性、癫痫易感性和癫痫与AD共病关系中的神经病理学。的 本研究的总体目标是确定神经雌二醇在调节细胞凋亡中的作用。 兴奋性、突触传递和癫痫发作易感性在AD小鼠模型中， 癫痫发作目的一：应用膜片钳电生理、生物化学、多标记免疫荧光技术， 显微镜下，和一种新的转基因小鼠模型，以确定神经雌二醇在调节细胞的作用， 兴奋性和突触传递在AD和对照小鼠的海马。在目标2中，我们将使用体内 视频脑电图和神经变性和神经胶质增生的组织学评估，以确定神经雌二醇的作用 在AD背景下调节癫痫发作易感性和癫痫诱导的神经病理学。这些研究将 通过对神经雌二醇在过度兴奋中的作用提供新的见解， 在男性和女性中，AD的癫痫发作，使开发新的治疗策略， 在最小化对认知的有害影响的同时，抑制神经功能的作用。

PROJECT SUMMARY Patients with Alzheimer Disease (AD) are at increased risk of seizures. Women show higher rates of AD than men, and loss of neuroprotective effects of ovarian hormones, such as estradiol, during and after menopause is considered to be a factor in cognitive and memory deficits of AD. However, estradiol is primarily linked to seizure- promoting effects in epilepsy. Estradiol thus may have both beneficial effects supporting cognitive function and detrimental (proconvulsant) effects in AD with comorbid seizures. Estradiol is synthesized from testosterone by the aromatase enzyme. Brain areas that are highly implicated in both AD and epilepsy, such as hippocampus and cortex, express high levels of aromatase in both males and females. Previous studies indicate that aromatase inhibition suppresses seizure susceptibility, but this effect has not been examined in the context of AD. Therefore, major gaps in knowledge remain regarding the role of brain-derived estradiol (neuroestradiol) in excitability, seizure susceptibility, and neuropathology in the comorbid relationship of seizures and AD. The overall objective of the proposed studies is to determine the role of neuroestradiol in modulating cellular excitability, synaptic transmission, and seizure susceptibility in a mouse model of AD that is prone to develop seizures. In Aim 1, we will use patch clamp electrophysiology, biochemistry, multilabel immunofluorescence microscopy, and a novel transgenic mouse model to determine the role of neuroestradiol in modulating cellular excitability and synaptic transmission in the hippocampus in AD and control mice. In Aim 2, we will use in vivo video-EEG and histological evaluation of neurodegeneration and gliosis to determine the role of neuroestradiol in modulating seizure susceptibility and seizure-induced neuropathology in the context of AD. These studies will have positive translational impact by providing new insights into the roles of neuroestradiol in hyperexcitability and seizures in AD in both males and females, enabling development of new therapeutic strategies to maximize seizure-suppressive effects while minimizing deleterious effects on cognition.