The excitatory peptide kisspeptin restores the luteinizing hormone surge and modulates amino acid neurotransmission in the medial preoptic area of middle-aged rats.
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.
Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Genevieve
G
Neal-Perry
Diane
D
Lebesgue
Matthew
M
Lederman
Jun
J
Shu
Gail D
GD
Zeevalk
Anne M
AM
Etgen
D000367:Age Factors; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D059648:Kisspeptins; D007986:Luteinizing Hormone / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011301:Preoptic Area / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D018696:Neuroprotective Agents; D011372:Progestins; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D011374:Progesterone; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; D007986:Luteinizing Hormone