Regulations of Neurotransmitter Action by Steroid Hormones in Females

描述（由申请方提供）：拟定研究的目的是解决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、妊娠以及应激与卵巢周期相互作用过程中GABA能抑制变化的机制。我们的实验将集中在调节GABAAR的表达和功能的孕酮及其神经类固醇代谢产物。我们最近证明了特定GABAAR表达和功能的动态卵巢周期相关修饰，而其他人则显示相同的受体在导水管周围灰质中平行卵巢周期变化或在PMS的类固醇戒断模型中上调。在小鼠动情间期，当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亚基的表达增加，齿状回颗粒细胞（DGGCs）中GABAAR 6亚基介导的紧张性抑制增加。GABAAR 6亚基的这种增加对应于癫痫易感性和焦虑降低的时期。该项目的具体目标将这些发现扩展到妊娠/产后期间GABAAR改变的研究以及压力与卵巢周期之间的相互作用。孕酮及其衍生物对GABAAR表达和功能调节的部分贡献将得到解决，并将研究影响GABA能系统变化的可能分子机制（局部受体合成和受体内化）。一种新的产后抑郁症小鼠模型将构成一个独特的机会，开始研究基本的神经元机制，这种精神疾病影响近10%的妇女在早期母亲。我们的一般假设是，生理和病理变化的内源性类固醇激素在女性大脑中改变神经元的兴奋性，通过产生激素的状态依赖性的变化，在特定的神经递质受体系统。本提案的重点是一般的GABA能抑制，特别是由6个含亚基的GABAAR介导的紧张性抑制，这些亚基是CNS中介导神经类固醇敏感性的首选（如果不是唯一的）位点。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，并将通过使用各种分子生物学，生物化学，电生理学和行为学方法来确定GABAAR中类固醇相关变化的机制。我们的研究与了解几种精神和神经系统疾病的病理学有关，包括经前焦虑症（PMDD），月经期癫痫和产后抑郁症，这些疾病都与女性激素水平的改变有关。揭示控制女性中GABAAR的神经介导调节的事件将导致新的和潜在的更有效的治疗靶点，用于治疗和最终预防这些神经和精神疾病，同时为人类功能和临床研究的新方法开辟道路。

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.