Regulations of Neurotransmitter Action by Steroid Hormones in Females

描述（由申请人提供）：拟议研究的目标是解决在类固醇激素水平改变期间女性大脑神经元兴奋性变化的基本过程。我们将探讨在卵巢周期、妊娠期以及应激与卵巢周期相互作用期间gaba能抑制变化的调控机制。我们的实验将重点关注孕激素及其神经类固醇代谢物对GABAAR表达和功能的调节。我们最近证明了动态的，卵巢周期相关的特异性GABAAR表达和功能的改变，而其他人已经表明相同的受体在输尿管周围灰质中平行卵巢周期变化或在经前综合征的类固醇戒断模型中上调。孕酮和孕酮衍生物神经甾体水平升高时，海马神经元中GABAAR 6亚基表达增加，齿状回颗粒细胞（DGGCs）中GABAAR 6亚基介导的强直抑制增加。GABAAR 6亚基的增加与癫痫易感性和焦虑降低的时期相对应。该项目的具体目的是将这些发现扩展到怀孕/产后GABAAR变化的研究以及压力与卵巢周期之间的相互作用。黄体酮及其衍生物对GABAAR表达和功能调控的部分贡献将得到解决，并将研究影响GABAAR能系统变化的可能的分子机制（局部受体合成和受体内化）。一种新型的产后抑郁症小鼠模型将为开始研究这种影响近10%的早期母亲的精神疾病的基本神经机制提供一个独特的机会。我们的一般假设是，女性大脑内源性类固醇激素的生理和病理变化通过在特定的神经递质受体系统中产生激素状态依赖的变化来改变神经元的兴奋性。本提案的重点是一般的gaba能抑制，特别是6亚基含GABAARs介导的强直抑制，这是首选的，如果不是唯一的，中枢神经系统中介导神经类固醇敏感性的部位。该项目将解决内源性孕酮在雌性小鼠GABAAR表达和功能中的作用，并将通过各种分子生物学，生化，电生理和行为方法确定类固醇激素相关GABAARs变化的机制。我们的研究与理解一些精神和神经疾病的病理有关，包括经前烦躁不安（PMDD）、睡眠性癫痫和产后抑郁症，这些疾病都与女性激素水平的改变有关。揭示控制女性GABAARs激素介导调节的事件将为治疗和最终预防这些神经和精神疾病带来新的和潜在的更有效的治疗靶点，同时为人类功能和临床研究开辟新的途径。

DESCRIPTION (provided by applicant): The goal of the proposed studies is to address fundamental processes underlying the changes in neuronal excitability in the female brain during periods of altered steroid hormone levels. We will explore the mechanisms governing changes in GABAergic inhibition during the ovarian cycle, pregnancy, and during the interaction between stress and the ovarian cycle. Our experiments will focus on the regulation of GABAAR expression and function by progesterone and its neurosteroid metabolites. We recently demonstrated dynamic, ovarian cycle-linked modifications in specific GABAAR expression and function, while others have shown the same receptors to parallel ovarian cycle changes in the periaqueductal grey matter or to be upregulated in a steroid withdrawal model of PMS. During diestrus in mice when levels of progesterone and of progesterone-derivatives neurosteroids are elevated, there is an increased expression: of the GABAAR 6 subunits in hippocampal neurons and an increase in GABAAR 6 subunit-mediated tonic inhibition in dentate gyrus granule cells (DGGCs). This increase in GABAAR 6 subunits corresponds to a period of lowered seizure susceptibility and anxiety. The specific aims of this project will extend these Findings to the study of GABAAR alterations during pregnancy/postpartum and to the interactions between stress and the ovarian cycle. The fractional contributions of progesterone and its derivatives to the regulation of GABAAR expression and function will be addressed and possible molecular mechanisms (local receptor synthesis and receptor internalization) underlying the changes affecting the GABAergic system will be studied. A novel mouse model of postpartum depression will constitute a unique opportunity to begin to study fundamental neuronal mechanisms underlying this psychiatric disorder affecting nearly 10% of women in early motherhood. Our general hypothesis is that physiological and pathological changes in endogenous steroid hormones in the female brain alter neuronal excitability by producing hormonal state-dependent changes in specific neurotransmitter receptor systems. The focus of the present proposal is GABAergic inhibition in general, and specifically the tonic inhibition mediated by 6 subunit-containing GABAARs, which are the preferred, if not the sole, site mediating neurosteroid sensitivity in the CNS. The project will address the role of endogenous progesterone in GABAAR expression and function in female mice and will identify mechanisms underlying steroid hormone-linked changes in GABAARs by using a variety of molecular biological, biochemical, electrophysiological and behavioral approaches. Our studies are relevant to understanding the pathology of several psychiatric and neurological disorders including pre-menstrual dysphoric disorder (PMDD), catamenial epilepsy, and postpartum depression that are all linked to alterations in hormone levels in women. Uncovering events controlling the hormone-mediated regulation of GABAARs in females will lead to novel and potentially more effective therapeutic targets for treating and ultimately preventing these neurological and psychiatric disorders, while opening the way for fresh approaches to functional and clinical studies in humans.