Tonic Control of Kisspeptin Release in Prepubertal Monkeys: Implications to the Mechanism of Puberty Onset

Wisconsin National Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, Wisconsin 53715-1299, USA.
Endocrinology (Impact Factor: 4.5). 05/2012; 153(7):3331-6. DOI: 10.1210/en.2012-1221
Source: PubMed

ABSTRACT Previously we have shown that a reduction in γ-amino butyric acid (GABA) inhibition is critical for the mechanism initiating puberty onset because chronic infusion of the GABA(A) receptor antagonist, bicuculline, significantly increased GnRH release and accelerated the timing of menarche and first ovulation in female rhesus monkeys. Because previous studies in our laboratory indicate that in prepubertal female monkeys, kisspeptin release in the medial basal hypothalamus is low, whereas kisspeptin-10 can stimulate GnRH release, we hypothesized that a low level of kisspeptin release prior to puberty onset is due to tonic GABA inhibition. To test this hypothesis we examined the effects of bicuculline infusion on kisspeptin release using a microdialysis method. We found that bicuculline at 1 μM dramatically stimulates kisspeptin release in the medial basal hypothalamus of prepubertal monkeys but had little effect on kisspeptin release in midpubertal monkeys. We further examined whether bicuculline-induced GnRH release is blocked by the presence of the kisspeptin antagonist, peptide 234. We found that inhibition of kisspeptin signaling blocked the bicuculline-induced stimulation of GnRH release, suggesting that kisspeptin neurons may relay inhibitory GABA signals to GnRH neurons. This implies that a reduction in tonic GABA inhibition of GnRH release is, at least in part, mediated through kisspeptin neurons.

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    • "In the female rhesus monkey, a very recent study demonstrated the fundamental role of GABA signaling in restraining kisspeptin release prior to puberty. GABAA receptor antagonist administration during the prepubertal period but not during the pubertal period stimulates kisspeptin release in the medial basal hypothalamus (Kurian et al., 2012). In the same study, the use of a GPR54 antagonist suggested that kisspeptin neurons may relay inhibitory GABA signals to GnRH neurons prior to puberty. "
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    ABSTRACT: The prominent role of the G protein coupled receptor GPR54 and its peptide ligand kisspeptin in the progression of puberty has been extensively documented in many mammalian species including humans. Kisspeptins are very potent gonadotropin-releasing hormone secretagogues produced by two main populations of neurons located in two ventral forebrain regions, the preoptic area and the arcuate nucleus. Within the last 2 years a substantial amount of data has accumulated concerning the development of these neuronal populations and their timely regulation by central and peripheral factors during fetal, neonatal, and peripubertal stages of development. This review focuses on the development of the kisspeptin-GPR54 system in the brain of female mice, rats, sheep, monkeys, and humans. We will also discuss the notion that this system represents a major target through which signals from the environment early in life can reprogram reproductive function.
    Frontiers in Endocrinology 03/2013; 4:22. DOI:10.3389/fendo.2013.00022
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    • "GABRA1 encodes the gamma amino butyric acid A1 receptor α-1 subunit, which is reported to be essential for the effects of the gamma-aminobutyric acid type A (GABAA) receptors on GnRH neurons (Lee et al., 2010). An interest in investigating GABAA receptors in girls with ICPP came from studies showing that a GABAA receptor antagonist (bicuculine) accelerated puberty in monkeys (Keen et al., 1999), and that this effect was mediated by kisspeptin as indicated by robust increases in kisspeptin secretion in response to bicuculine (Kurian et al., 2012). Also, the effect of bicuculine on GnRH neurons was prevented by pre-treatment with anti-kisspeptin serum (Terasawa et al., 2010; Kurian et al., 2012). "
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    ABSTRACT: The major determinants of the variability in pubertal maturation are reported to be genetic and inherited. Nonetheless, nutritional status contributes significantly to this variability. Malnutrition delays puberty whereas obesity has been associated to a rise in Idiopathic Central Precocious Puberty (ICPP) in girls. However, epidemiology data indicate that contribution of obesity to early puberty varies significantly among ethnic groups, and that obesity-independent inheritable genetic factors are the strongest predictors of early puberty in any ethnic group. In fact, two human mutations with confirmed association to ICPP have been identified in children with no history of obesity. These mutations are in kisspeptin and kisspeptin receptor, a ligand/receptor pair with a major role on the onset of puberty and female cyclicity after puberty. Progressive increases in kisspeptin expression in hypothalamic nuclei known to regulate reproductive function has been associated to the onset of puberty, and hypothalamic expression of kisspeptin is reported to be sexually dimorphic in many species, which include humans. The hypothalamus of females is programmed to express significantly higher levels of kisspeptin than their male counterparts. Interestingly, incidence of ICPP and delayed puberty in children is markedly sexually dimorphic, such that ICPP is at least 10-fold more frequent in females, whereas prevalence of delayed puberty is about 5-fold higher in males. These observations are consistent with a possible involvement of sexually dimorphic kisspeptin signaling in the sexual dimorphism of normal puberty and of pubertal disorders in children of all ethnicities. This review discusses the likelihood of such associations, as well as a potential role of kisspeptin as the converging target of environmental, metabolic, and hormonal signals, which would be integrated in order to optimize reproductive function.
    Frontiers in Endocrinology 12/2012; 3:149. DOI:10.3389/fendo.2012.00149
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    ABSTRACT: Puberty is a fascinating developmental phase that involves the attainment of reproductive capacity and the completion of sexual and somatic maturation. As life-changing event, puberty onset is precisely controlled by interconnected regulatory pathways that are sensitive to numerous endogenous signals and environmental cues. The mechanisms of normal puberty and its potential deviations have been thoroughly studied in humans and model species. Yet, characterization of the neurobiological basis of puberty is still incomplete. Progress in this front is not only relevant from a physiological perspective but would help also to unravel the underlying causes for the observed changes in the timing of puberty in humans, with a trend for earlier puberty onset, especially in girls. In this review, we will provide a synoptic overview of some recent developments in the field that have deepened our understanding of the neuroendocrine and molecular basis for the control of puberty onset. These include not only the demonstration of the involvement of the hypothalamic Kiss1 system in the control of puberty and its modulation by metabolic cues, but also the identification of the roles of other neuropeptide pathways and molecular mediators in the regulation of puberty. In addition, the potential contribution of novel regulatory mechanisms, such as epigenetics, in the central control of puberty will be briefly discussed. Characterization of these novel players and regulatory mechanisms will improve our understanding of the basis of normal puberty, and its eventual alterations in various pathological conditions.
    European Journal of Endocrinology 09/2012; 167(6). DOI:10.1530/EJE-12-0669 · 4.07 Impact Factor
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