Novel Mechanisms Underlying the Transsynaptic Control of LHRH Release

黄体生成素释放激素（LHRH）的分泌受兴奋性和抑制性跨突触输入以及gila-to-neuron信号通路的控制。虽然利用伽马氨基丁酸（GABA）进行突触通讯的神经元为LHRH神经元网络提供了主要的抑制性输入，但LHRH释放的大部分兴奋性控制是由使用谷氨酸进行神经传递的神经元回路提供的。在过去的支持期间，我们将注意力集中在GABAA能系统上，并证明-与主流教条相反-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。利用基因转移细胞移植技术和转基因方法，我们证明了gaba能张力是LHRH神经元正常迁移和成年女性生殖能力所必需的。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来确定这种机制在控制成人LHRH神经元功能中的重要性。此外，我们使用基因发现方法来鉴定似乎是LHRH神经分泌双抑制性/兴奋性跨突触控制的上游成分的基因。现在，研究人员提出要确定这些调节成分对女性成年期LHRH神经元功能能力的影响。为此，我们提出了以下目的：1)验证直接施加于LHRH神经元的兴奋性gabaar介导的输入是正常生殖周期所必需的假设；2)确定小说成员的作用

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.