GABAERGIC CONTROL OF LHRH NEURONAL FUNCTION

伽马氨基丁酸（Gamma aminobutyric acid， 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分泌中起着突出作用。现在看来，通过GABA/ a受体（GABA- ar）施加的GABA能控制在LHRH神经元发育的早期建立，并继续在LHRH神经元网络的自然历史中发挥作用。很可能这种调节影响的一部分直接作用于LHRH神经元，因为它们表达功能GABA-AR组装所需的所有受体亚基。虽然最近的研究表明GABA-AR激活对LHRH神经元迁移有调节作用，但这种作用是否直接作用于LHRH神经元尚不清楚。同样，对于gaba能神经支配LHRH神经元可能对成人生殖功能的控制的生理影响，我们也一无所知。由于GABA影响神经元回路的复杂性和GABA- ar系统的分子复杂性，传统的神经内分泌实验很难解决这些问题。最近遗传方法的发展以细胞特异性和时间限制性的方式修饰基因表达，以及gaba - ar介导的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揭示gaba能控制生殖功能的一些基本机制。在这项研究中，我们提出结合遗传和神经内分泌的方法来确定GABA对LHRH神经元胚胎发育和成年期LHRH神经元网络功能能力的贡献。为此，我们提出以下目的来验证以下假设：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神经元接受gaba - ar介导的直接输入是LHRH神经元网络正常生殖周期所需的调节成分。3)选择性破坏LHRH神经元中GABA- ar β /3亚基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灵长类动物的月经周期，从而在实验环境中重现人类下丘脑闭经综合征。我们预计这些研究将有助于更好地理解下丘脑闭经和特发性下丘脑性腺功能减退等人类综合征中生殖能力丧失的细胞机制。

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.