GABAergic regulation of hypotalamic-pituary axis and its role in the metabolic control of fertility

Sexual maturation and fertility are fundamental physiological functions and their regulation has the final purpose to ensure the optimal reproductive capacity. Central and peripheral regulatory signals, such as neuronal peptides and sex steroids, converge on GnRH neurons which are the hierarchical key cellular components of the hypothalamic-pituary-gonadal (HPG) axis. The finding that these regulators do not act directly on GnRH neurons has prompted new researches on others upstream neural networks which integrate peripheral information and modulate GnRH activity. In this complex system, GABAergic neurons are essential to maintain the peculiar secretion pattern of GnRH. Electrophysiological analysis demonstrated that the GABAergic activity is estradiol- and time of day-sensitive and results in a specific modulation of Kisspeptin neurons, strong activators of GnRH, allowing the correct proceeding of every phase of reproductive cycle. Moreover, the GABAergic system plays an important role in the integration and transmission of the metabolic information conveyed by leptin to the hypothalamic network underlying sexual maturation and fertility. Murine models in which selective ablation of leptin receptor in both glutamatergic and GABAergic neurons was performed, demonstrate the primary role of leptin-responsive GABAergic neurons in the modulation of Kisspeptin neurons and consequently of GnRH secretion. Supporting this thesis, Agouti-related peptide (AgRP)-expressing neurons, which co-express GABA, are strongly leptin-sensitive and low leptin levels enhanced their inhibitory activity on Kisspeptin. The final effect is the impairment of correct GnRH pulse which results in a condition of infertility. All these data highlight the complexity of this network and that the integration of several stimuli is required for the correct functioning of reproductive efficiency.