Luteinizing hormone-releasing hormone (LHRH) secretion is controlled by transsynaptic inputs of both excitatory and inhibitory nature, in addition to gila-to-neuron signaling pathways. While neurons that utilize gamma aminobutydc acid (GABA) for synaptic communication provide the major inhibitory input to the LHRH neuronal network, the bulk of the excitatory control of LHRH release is furnished by neuronal circuitries that use glutamate for neurotransmission. During the past period of support we focused our attention on the GABAergic system, and demonstrated that - contrary to the prevailing dogma - the direct GABAA receptor (R)-mediated input to LHRH neurons is excitatory, and not inhibitory. Using gene transfercell 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 prepared the molecular and genetic reagents to define the importance of such mechanisms in the control of adult LHRH neuronal function. In addition, we used gene discovery approaches to identify genes that appear to be upstream components of the dual inhibitory/excitatory transsynaptic control of LHRH neurosecretion. Studies are now proposed to define the impact that each of these regulatory components may exert on the functional competence of LHRH neurons during female adulthood. To this end, the following aims are proposed: 1) to test the hypothesis that excitatory GABAAR-mediated inputs exerted directly on LHRH neurons are required for normal reproductive cyclicity, 2) to determine the role that members of the novel FXYD family of ion transport-controlling proteins, play in the regulation of LHRH secretion, 3) to test the hypothesis that Nell2, a novel gene specifically expressed in glutamatergic neurons, is an upstream regulatory element required for the glutamatergic control of reproduction, and 4) to define the role that a novel gene known as C14ORF4 may play 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.
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