NOVEL MECHANISMS UNDERLYING THE TRANSSYNAPTIC CONTROL OF LHRH RELEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 黄体生成素释放激素(LHRH)的分泌受兴奋性和抑制性的跨突触输入以及神经胶质细胞到神经元信号通路的控制。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输入。我们已经证明，与流行的教条相反，GABAA受体(R)介导的直接LHRH神经元输入是兴奋性的，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神经元迁移和成年雌性生殖能力正常所必需的。我们还确定了GABAAR介导的LHRH神经元兴奋的细胞机制，并确定了似乎是双重抑制/兴奋性跨突触控制LHRH分泌的上游成分的基因。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。正在测试的假设包括：1)GABAAR介导的兴奋性输入直接作用于LHRH神经元是正常生殖周期所必需的，2)新的FXYD离子转运控制蛋白家族的成员在LHRH分泌的调节中发挥作用，3)Nell2，一个在谷氨酸能神经元中特异表达的新基因，是谷氨酸能控制生殖所必需的上游调节元件，以及4)一个被称为C14ORF4的新基因在协调对生殖周期的双重兴奋/抑制跨突触控制中发挥作用。来自这些研究的概念有望增加我们对人类综合征(如下丘脑闭经和特发性下丘脑低性腺机能减退)生殖能力丧失的细胞机制的理解。

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. The concepts derived from these studies are expected to increase our understanding of the cellular mechanisms underlying the loss of reproductive competence in human syndromes such as hypothalamic amenorrhea and idiopathic hypothalamic hypogonadism.