Uncovering Novel Reproductive Defects in Neurokinin B Receptor Null Mice: Closing the Gap Between Mice and Men

Yang, Jasmine J.; Caligioni, Claudia S.; Chan, Yee-Ming; Seminara, Stephanie B.

doi:10.1210/en.2011-1949

Cited by 106 publications

(85 citation statements)

References 59 publications

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“…found to coexpress another neuromodulator implicated in the regulation of gonadotrope axis, neurokinin B (16,17). Thus, we also measured Tac2 gene and protein (NKB) expression, which was not altered after PRL administration ( Figure 2F and Supplemental Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

Sonigo¹,

Bouilly²,

Carré³

et al. 2012

J. Clin. Invest.

166

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Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists. IntroductionHyperprolactinemia is the most common cause of hypogonadotropic anovulation (WHO Group I) and represents a major etiology of infertility, with highest incidence in women aged 25-34 years (1). In men, hyperprolactinemia is also frequently associated with hypogonadotropic hypogonadism. This gonadotropic deficiency has been proposed to result from direct suppression of prolactin (PRL) on gonadotrophin-releasing hormone (GnRH) release, but evidence supporting this mechanism has never been provided. PRL is synthesized and secreted by the lactotrope cells of the pituitary, and high levels of circulating PRL are mainly caused by lactotroph adenomas, which account for approximately 40% of all pituitary tumors. Pulsatile GnRH replacement can reverse hypogonadotropic hypogonadism and infertility induced by hyperprolactinemia in women as well as men (2, 3), suggesting that PRL excess in humans affects hypothalamic release of GnRH rather than directly affecting pituitary or gonad function. However, very few GnRH neurons in mice express PRL receptors (PRLRs) (4), suggesting that PRL exerts its actions on upstream neurons regulating the GnRH neuron. Because GnRH neurons are stimulated by kisspeptin (Kp) neurons (5, 6), which unequivocally express PRLR (7), we hypothesized that GnRH deficiency resulting from hyperprolactinemia is caused by reduced Kp input, which is now considered to be a primary gatekeeper governing reproduction (8,9). Here, we show that hyperprolactinemia in mice induces hypogonadotropic anovulation and diminished Kp expression and that peripheral Kp administration restores GnRH and gonadotropin secretion and ovarian cyclicity. Therefore, we suggest that hyperprolactinemic women resistant or intolerant to dopamine agonists could take advantage of this therapeutic approach as a treatment for their infertility.

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Section: Resultsmentioning

confidence: 99%

Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

Sonigo¹,

Bouilly²,

Carré³

et al. 2012

J. Clin. Invest.

166

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“…The translational relevance of such coexpression, and of NKB actions in the reproductive brain, is reinforced by data from human studies that demonstrated that lossof-function mutations in the genes encoding either NKB (TAC3 in humans) or its receptor, NK3R (TAC3R in humans), are associated with impuberism and iHH (29,30,31), a phenotype similar to that of GPR54 or KISS1 null humans (10). Yet, NK3R null mice appear to display normal pubertal timing in males and females (32). To add further complexity, dynorphin-A (Dyn) and NK3R have also been found in Kiss1/NKB expressing neurons (25); Kiss1/NKB/Dyn colocalization being a specific feature of the ARC/infundibular population of Kiss1 neurons, which has been renamed as KNDy to emphasize the potential usage of these three neuropeptides (23).…”

Section: Kisspeptins: Major Gatekeepers Of Pubertymentioning

confidence: 99%

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

Tena‐Sempere

2012

European Journal of Endocrinology

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Puberty is a fascinating developmental phase that involves the attainment of reproductive capacity and the completion of sexual and somatic maturation. As a 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 on this front is not only relevant from a physiological perspective but would also help 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 167 733-747

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“…In a human sample of 209 patients who all exhibited cognitive impairments, we found that the r2765 SNP in the TACR3 gene predicted the degree of learning and memory impairment in two neuropsychological tests of word-list learning. Mutations in the human TACR3 gene have been shown to play an important role in puberty development and are associated with hypogonadotrophic hypogonadism (40). An association with cognitive performance has also been suggested by animal studies using NK3-R knockout mice (15).…”

Section: Discussionmentioning

confidence: 99%

Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism

Silva

Lenz

Rotter

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism. senktide | in vivo microdialysis H umans exhibit a decline in cognitive capacity with age, which may progressively lead to dementia (1). Age-dependent morphological and physiological changes within the cholinergic system of the brain have been described as a major mechanism underlying impairments of learning and memory (2, 3). Numerous studies in aged rats have revealed that a degeneration of cholinergic neurons in the basal forebrain is associated with learning and >memory deficits (4). Likewise, the consistent correlations found between cholinergic degeneration and cognitive impairments indicate a high correspondence between acetylcholinergic activity and the magnitude of cognitive decline (4-6). This relationship has also been shown in patients with Alzheimer's disease (7,8).The neuropeptide neurokinins (NKs) substance P, neurokinin A, neurokinin B (NK-B), neuropeptide K, neuropeptide γ, and hemokinin 1 bind to the three known NK-receptors (NK3-R) (NK1-, NK2-, and NK3-R) with different degrees of affinity, whereby NK-B is the preferred ligand to NK3-R (9). NK3-Rs are widespread in the brain, including areas that are implicated in processes governing learning and memory such as the hippocampus, frontal cortex (FC), and medial septum (10, 11). There is a close interaction between NK3-R and the cholinergic system. NK3-R are localized on cholinacetyltransferase-containing neurons in ...

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Uncovering Novel Reproductive Defects in Neurokinin B Receptor Null Mice: Closing the Gap Between Mice and Men

Cited by 106 publications

References 59 publications

Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism

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