NOVEL MECHANISMS UNDERLYING THE TRANSSYNAPTIC CONTROL OF LHRH RELEASE

促黄体生成素释放激素(LHRH)的分泌由两者的跨突触输入控制 兴奋性和抑制性，以及GILA到神经元的信号通路。而神经元则利用 伽玛氨基丁酸(GABA)为突触通讯提供了主要的抑制输入。 LHRH神经元网络，LHRH释放的大部分兴奋控制是由神经元提供的 使用谷氨酸进行神经传递的电路。在过去的支持期间，我们将重点放在了 对GABA能系统的关注，并证明了-与流行的教条相反-直接 GABAA受体(R)介导的LHRH神经元输入是兴奋性的，而不是抑制性的。使用基因转移细胞 嫁接技术和转基因方法我们证明了GABA能激素是 LHRH神经元迁移和成年女性生殖能力的正常。我们还确认了 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控制成年LHRH神经元功能中的重要性。此外，我们使用基因发现方法来识别似乎是LHRH神经分泌双重抑制/兴奋性跨突触控制的上游成分的基因。 现在有人提议进行研究，以确定这些调节成分中的每一个可能对女性成年期LHRH神经元的功能能力产生的影响。为此，我们提出了以下目标：1)检验兴奋性GABAAR介导的直接作用于LHRH神经元的兴奋性输入是正常生殖周期所必需的假设，2)确定新的离子转运控制蛋白FXYD家族的成员在调节LHRH分泌中所起的作用，3)检验Nell2这一在谷氨酸能神经元中特异表达的新基因是生殖控制所需的上游调控元件的假设，以及4)确定一个被称为C14ORF4的新基因在协调双重兴奋性/抑制性跨突触控制生殖周期性中所起的作用。我们期待从这些研究中得出的概念将有助于更好地理解人类综合征中生殖能力丧失的细胞机制，如下丘脑闭经和特发性下丘脑性腺功能低下症。

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.