GABAERGIC CONTROL OF LHRH NEURONAL FUNCTION

LHRH 神经元功能的 GABA 能控制

基本信息

批准号：
6584205
负责人：
Sergio R Ojeda
金额：
$ 17.42万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2003-03-31
项目状态：
已结题

项目摘要

Gamma aminobutyric acid (GABA), the dominant inhibitory neurotransmitter in the central nervous system plays a prominent role in the control of hypothalamic LHRH secretion. It now appears that a GABAergic control exerted via GABA/A receptors (GABA-AR) is established during early LHRH neuronal development and continues to operate throughout the natural history of the LHRH neuronal network. It is likely that part of this regulatory influence is exerted directly on LHRH neurons, as they express all of the receptor subunits required for the assembly of functional GABA-AR. Although recent studies have demonstrated a modulatory effect of GABA-AR activation on LHRH neuronal migration, it is not known if such an effect is directly exerted on LHRH neurons. Likewise, nothing is known about the physiological impact that the GABAergic innervation on LHRH neurons may have on the control of adult reproductive function. Resolution of these issues by conventional neuroendocrine experimentation is difficult, because of the intricacy of the neuronal circuities affected by GABA and the molecular complexity of the GABA-AR system. The recent development of genetic approaches to modify the expression of genes in a cell-specific and temporally- restricted manner, and the identification of some of the key components involved in GABA-AR-mediated signaling, provide us with a unique opportunity to unravel some of the basic mechanisms underlying the GABAergic control of reproductive function. In this study, we propose a combination of genetic and neuroendocrine approaches to define the contribution of GABA to the embryonic development of LHRH neurons and to the functional competencies of the LHRH neuronal network during adulthood. To this end, the following aims are proposed to test the hypotheses that: 1) Direct GABAergic excitatory inputs play a role in the migration and developmental rate of LHRH neurons. 2) The direct GABA-AR-mediated input received by adult LHRH neurons is a regulatory component of the LHRH neuronal network required for normal reproductive cyclicity. 3) Selective disruption of the GABA-AR beta/3 subunit in LHRH neurons results in hypothalamic hypogonadism, and 4) A site- and time- specific, reversible activation of GABA release suffices to disrupt menstrual cyclicity in non-human primates, thus re-creating in an experimental setting the human syndrome of hypothalamic amenorrhea. We anticipate that these studies will lead to a better understanding of the cellular mechanisms underlying the central loss of reproductive competence in human syndromes such as hypothalamic amenorrhea and idiopathic hypothalamic hypogonadism.

γ-氨基丁酸 (GABA) 是中枢神经系统中主要的抑制性神经递质，在控制下丘脑 LHRH 分泌中发挥着重要作用。现在看来，通过 GABA/A 受体 (GABA-AR) 发挥的 GABA 能控制是在早期 LHRH 神经元发育过程中建立的，并且在 LHRH 神经元网络的整个自然历史中持续发挥作用。这种调节影响的一部分很可能直接作用于 LHRH 神经元，因为它们表达组装功能性 GABA-AR 所需的所有受体亚基。尽管最近的研究已经证明 GABA-AR 激活对 LHRH 神经元迁移具有调节作用，但尚不清楚这种作用是否直接作用于 LHRH 神经元。同样，对于 LHRH 神经元上的 GABA 能神经支配可能对成人生殖功能的控制产生的生理影响也一无所知。由于受 GABA 影响的神经元回路的复杂性以及 GABA-AR 系统的分子复杂性，通过传统的神经内分泌实验解决这些问题很困难。最近以细胞特异性和时间限制的方式修饰基因表达的遗传方法的发展，以及 GABA-AR 介导信号传导中涉及的一些关键成分的鉴定，为我们提供了一个独特的机会来解开一些问题。 GABAergic 控制生殖功能的基本机制。在这项研究中，我们提出了遗传和神经内分泌方法相结合的方法来确定 GABA 对 LHRH 神经元胚胎发育以及成年期 LHRH 神经元网络功能的贡献。为此，提出以下目标来检验以下假设：1）直接GABA能兴奋性输入在LHRH神经元的迁移和发育速率中发挥作用。 2) 成人 LHRH 神经元接收的直接 GABA-AR 介导的输入是正常生殖周期所需的 LHRH 神经元网络的调节组件。 3) LHRH 神经元中 GABA-AR beta/3 亚基的选择性破坏导致下丘脑性腺功能减退，4) GABA 释放的位点和时间特异性、可逆激活足以破坏非人类灵长类动物的月经周期，从而重新激活 GABA 释放。 -在实验环境中创造人类下丘脑闭经综合症。我们预计这些研究将有助于更好地理解人类综合征（如下丘脑闭经和特发性下丘脑性腺功能减退症）生殖能力中枢丧失的细胞机制。