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中神经元兴奋性变化的基本过程。我们将探索在卵巢周期、妊娠以及应激和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孕酮及其神经类固醇代谢物对GABAAR表达和功能的调节。我们最近展示了特定GABAAR表达和功能的动态、卵巢周期相关的改变，而其他受体在导水管周围灰质的平行卵巢周期变化中，或者在激素停药的经前综合征模型中上调。在发情间期，当孕酮和孕酮衍生物神经类固醇水平升高时，海马神经元中GABAAR6亚单位的表达增加，齿状回颗粒细胞(DGGCs)中GABAAR6亚单位介导的紧张性抑制增加。GABAAR 6亚单位的这种增加对应于癫痫敏感性和焦虑症的降低时期。该项目的具体目标将把这些发现扩展到对妊娠/产后GABAAR变化的研究，以及压力和卵巢周期之间的相互作用。将讨论孕酮及其衍生物对GABAAR表达和功能调节的部分贡献，并将研究影响GABAAR能系统变化的可能分子机制(局部受体合成和受体内化)。一种新的产后抑郁小鼠模型将构成一个独特的机会，可以开始研究这种精神障碍背后的基本神经机制，这种精神障碍影响着近10%的早期母亲。我们的一般假设是，女性大脑中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。本研究的重点是GABA能抑制，特别是由6个含GABA亚基的GABA受体介导的紧张性抑制，这是中枢神经系统中调节神经类固醇敏感性的首选部位，如果不是唯一的话。该项目将探讨内源性孕酮在雌性小鼠GABAAR表达和功能中的作用，并将利用各种分子生物学、生化、电生理和行为方法确定GABAAR中类固醇激素相关变化的机制。我们的研究与了解几种精神和神经疾病的病理有关，包括经前焦虑症(PMDD)、月经性癫痫和产后抑郁症，所有这些都与女性激素水平的变化有关。揭示控制女性体内激素介导的GABAARs调节的事件将导致治疗并最终预防这些神经和精神疾病的新的、可能更有效的治疗目标，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.