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: 8125590
• 负责人: Sergio R Ojeda
• 金额: $ 7.56万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125590
• 关键词: Acids; Adult; Amenorrhea; Amino Acid Neurotransmitters; Attention; Behavior; Brain; Cells; Communication; Competence; Coupled; DNA; DNA Microarray Chip; Family; Female; Gene Transfer; Genes; Glutamate Transporter; Glutamates; Gonadotropin Hormone Releasing Hormone; Human; Hypothalamic structure; Integral Membrane Protein; Interneurons; Ion Transport; Kallmann Syndrome; Lead; Mediating; Modeling; Molecular; Molecular Genetics; Monkeys; Nature; Neurons; Neurosecretion; Normalcy; Open Reading Frames; Periodicity; Play; Primates; Proteins; Rattus; Reagent; Regulation; Regulatory Element; Reproduction; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Synapses; Syndrome; System; Techniques; Testing; Transgenic Organisms; base; cDNA Arrays; gain of function; gene discovery; mRNA Differential Displays; member; migration; nerve supply; neuronal circuitry; neuronal excitability; neurotransmission; novel; postsynaptic; receptor; reproductive; research study; response

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 transfercell 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）的分泌受两个神经元的跨突触输入控制。 兴奋性和抑制性，除了神经胶质细胞到神经元的信号传导途径。当神经元利用 γ-氨基丁酸（GABA）的突触通讯提供了主要的抑制输入， 在LHRH神经元网络中，LHRH释放的大部分兴奋性控制由神经元提供。 利用谷氨酸进行神经传递的电路。在过去的支持期间，我们将重点放在 注意GABA能系统，并证明-与流行的教条相反-直接 GABAA受体（R）介导的输入LHRH神经元是兴奋性的，而不是抑制性的。使用基因转移细胞 我们通过嫁接技术和转基因方法证明， LHRH神经元迁移和成年雌性生殖能力的正常性。我们还确定 GABAAR介导的LHRH神经元兴奋的细胞机制，并制备分子和遗传试剂，以确定这种机制在成人LHRH神经元功能控制中的重要性。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，提出了以下目标：1）检验直接作用于LHRH神经元的兴奋性GABAAR介导的输入是正常生殖周期所需的假设，2）确定离子转运控制蛋白的新FXYD家族成员在调节LHRH分泌中的作用，3）检验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，以及4）确定一种称为C14 ORF 4的新基因在协调生殖周期性的双重兴奋性/抑制性跨突触控制中可能发挥的作用。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。