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.
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