GABAERGIC CONTROL OF LHRH NEURONAL FUNCTION (U54 PROJECT)

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 促黄体生成激素释放激素（LHRH）的分泌除了受神经胶质细胞-神经元信号通路的控制外，还受兴奋性和抑制性的跨突触输入的控制。利用γ-氨基丁酸（GABA）进行突触通讯的神经元为LHRH神经元网络提供了主要的抑制性输入。我们已经证明，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，并确定了似乎是LHRH分泌的双重抑制/兴奋性跨突触控制的上游组件的基因。 目前正在进行研究，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。 正在检验的假设包括：1）直接作用于LHRH神经元上的兴奋性GABAAR介导的输入是正常生殖周期所需的，2）离子转运控制蛋白的新FXYD家族的成员在LHRH分泌的调节中起作用，3）Nell 2，一种特异性表达于多巴胺能神经元中的新基因，是多巴胺能控制生殖所需的上游调节元件，和4）一种新的基因C14 ORF 4在协调生殖周期的双重兴奋/抑制跨突触控制中起作用。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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Luteinizing hormone-releasing hormone (LHRH) secretion is controlled by transsynaptic inputs of both excitatory and inhibitory nature, in addition to glia-to-neuron signaling pathways. Neurons that utilize gamma aminobutyric acid (GABA) for synaptic communication provide the major inhibitory input to the LHRH neuronal network. We have 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 identified genes that appear to be upstream components of the dual inhibitory/excitatory transsynaptic control of LHRH secretion. Studies are now being conducted to define the impact that each of these regulatory components may exert on the functional competence of LHRH neurons during female adulthood. The hypotheses being tested include: 1) that excitatory GABAAR-mediated inputs exerted directly on LHRH neurons are required for normal reproductive cyclicity, 2) that members of the novel FXYD family of ion transport-controlling proteins play in the regulation of LHRH secretion, 3) that Nell2, a novel gene specifically expressed in glutamatergic neurons, is an upstream regulatory element required for the glutamatergic control of reproduction, and 4) that a novel gene known as C14ORF4 plays a role 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.