Novel Mechanisms Underlying the Transsynaptic Control of LHRH Release

LHRH 释放的跨突触控制的新机制

• 批准号: 7004278
• 负责人: Sergio R Ojeda
• 金额: $ 16.97万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7004278
• 关键词: GABA receptor; cooperative study; electrophysiology; female reproductive system; gamma aminobutyrate; gene expression; genetically modified animals; glutamates; gonadotropin releasing factor; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory mouse; neural transmission; polymerase chain reaction; synapses; western blottings

Luteinizing hormone-releasing hormone (LHRH) secretion is controlled by transsynaptic inputs of both excitatory and inhibitory nature, in addition to gila-to-neuron signaling pathways. While neurons that utilize gamma aminobutydc acid (GABA) for synaptic communication provide the major inhibitory input to the LHRH neuronal network, the bulk of the excitatory control of LHRH release is furnished by neuronal circuitries that use glutamate for neurotransmission. During the past period of support we focused our attention on the GABAergic system, and demonstrated that - contrary to the prevailing dogma - the direct GABAA receptor (R)-mediated input to LHRH neurons is excitatory, and not inhibitory. Using gene transfer-cell grafting techniques and transgenic approaches we demonstrated that a GABAergic tone is required for the normalcy of both LHRH neuronal migration and adult female reproductive capacity. We also identified the cellular mechanisms underlying the GABAAR-mediated excitation of LHRH neurons, and prepared the molecular and genetic reagents to define the importance of such mechanisms in the control of adult LHRH neuronal function. In addition, we used gene discovery approaches to identify genes that appear to be upstream components of the dual inhibitory/excitatory transsynaptic control of LHRH neurosecretion. Studies are now proposed to define the impact that each of these regulatory components may exert on the functional competence of LHRH neurons during female adulthood. To this end, the following aims are proposed: 1) to test the hypothesis that excitatory GABAAR-mediated inputs exerted directly on LHRH neurons are required for normal reproductive cyclicity, 2) to determine the role that members of the novel FXYD family of ion transport-controlling proteins, play in the regulation of LHRH secretion, 3) to test the hypothesis that Nell2, a novel gene specifically expressed in glutamatergic neurons, is an upstream regulatory element required for the glutamatergic control of reproduction, and 4) to define the role that a novel gene known as C14ORF4 may play in coordinating the dual excitatory/inhibitory transsynaptic control of reproductive cyclicity. We anticipate that the concepts derived from these studies will lead to a better understanding of the cellular mechanisms underlying the loss of reproductive competence in human syndromes such as hypothalamic amenorrhea and idiopathic hypothalamic hypogonadism.

促黄体生成激素释放激素（LHRH）的分泌除了通过神经胶质细胞-神经元信号通路外，还受到兴奋性和抑制性的跨突触输入的控制。虽然利用γ-氨基丁酸（GABA）进行突触通讯的神经元为LHRH神经元网络提供主要的抑制性输入，但LHRH释放的大部分兴奋性控制由使用谷氨酸进行神经传递的神经元回路提供。在过去的支持期间，我们将注意力集中在GABA能系统上，并证明-与流行的教条相反-GABAA受体（R）介导的对LHRH神经元的直接输入是兴奋性的，而不是抑制性的。使用基因转移细胞移植技术和转基因方法，我们证明，GABA能的音调是需要的LHRH神经元迁移和成年女性生殖能力的正常。我们还确定了GABAAR介导的LHRH神经元兴奋的细胞机制，并制备了分子和遗传试剂，以确定这种机制在控制成人LHRH神经元功能中的重要性。此外，我们使用基因发现的方法来确定基因，似乎是上游组件的双重抑制/兴奋性跨突触控制LHRH神经分泌。现在提出的研究，以确定的影响，这些监管组件可能会施加在女性成年LHRH神经元的功能能力。为此，提出了以下目的：1）测试兴奋性GABAAR介导的输入直接施加在LHRH神经元上是正常生殖周期所需的假设，2）确定新的GABAAR成员的作用， FXYD家族的离子转运控制蛋白，在LHRH分泌的调节中起作用，3）为了验证Nell 2（一种在多巴胺能神经元中特异性表达的新基因）是多巴胺能控制生殖所需的上游调节元件的假设，和4）确定一种新的基因C14 ORF 4在协调双兴奋性/抑制性跨突触控制生殖周期。我们预计，从这些研究中得出的概念将导致更好地了解人类综合征，如下丘脑性闭经和特发性下丘脑性腺功能减退症的生殖能力丧失的细胞机制。