The Excitatory Peptide Kisspeptin Restores the Luteinizing Hormone Surge and Modulates Amino Acid Neurotransmission in the Medial Preoptic Area of Middle-Aged Rats

Abstract

Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and gamma-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-D-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.

Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1

“…Interestingly, cumulus and mural GCs have been shown to reflect the characteristics of the oocyte thus providing a noninvasive means to assess oocyte quality [35]. Our current findings suggest that in an infertile population, agerelated upregulation in kiss1r expression may alter kisspeptin sensitivity in human cumulus GCs indicating a possible agerelated physiologic role, similar to that observed in the hypothalamus [7,8], for the kisspeptin system in human follicular dynamics. These findings were supported by current data from mice where old mice had significantly higher kiss1 and kiss1r in their ovaries compared to younger reproductive-aged mice.…”

“…We and others have documented that reproductive aging is characterized by reduced hypothalamic kiss1 expression [7,8]. On the other hand, women with diminished ovarian reserve have a significant increase in ovarian sympathetic nerve fibers [9] whose stimulation with β-adrenergic agonist induces ovarian kiss1 expression [4].…”

“…The excitatory neuropeptide kisspeptin (kiss1) and its G protein-coupled receptor (kiss1r) are essential for the regulation of gonadotropin-releasing hormone (GnRH) neurons and puberty [1][2][3]. Additional actions of kiss1 at the level of the ovaries have been suggested [3][4][5][6] but remain scarcely studied.…”

Ovarian function and reproductive senescence in the rat: role of ovarian sympathetic innervation

“…Thus, the lower oestradiol levels and the low sensitivity to oestradiol may be the cause of the reduction in kisspeptin expression (Kermath et al 2014) and, consequently, irregular and lower GnRH/LH surges in aged rats. This suggestion is supported by the fact that kisspeptin infusion directly into the medial preoptic area restores the attenuated LH surge in middle-aged rats (Neal-Perry et al 2009). In addition to the failure in the kisspeptin system, other mechanisms could explain the alteration in GnRH/LH secretion.…”

Differential modulation of gonadotropin responses to kisspeptin by aminoacidergic, peptidergic, and nitric oxide neurotransmission

“…Among the potential interactive partners of Kp in the central control of the gonadotropic axis, their interplay with aminoacidergic neurotransmission has been investigated (7,10,35,38,39). Besides their well-known functions as major regulators of GnRH secretion, excitatory and inhibitory amino acids, such as glutamate and GABA, have been proposed to interact with Kp signaling in the regulation of GnRH release (20,21).…”