Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse

• Published in: Endocrinology (Philadelphia) 2017-07, Vol.158 (7), p.2319-2329
• Main Authors: Maguire, Caroline A., Song, Yong Bhum, Wu, Min, León, Silvia, Carroll, Rona S., Alreja, Meenakshi, Kaiser, Ursula B., Navarro, Víctor M.
• Format: Article
• Language: English
• Subjects: Agonists; Animals; Dynorphin; Electrophysiological Phenomena - drug effects; Endocrinology; Female; Glutamate receptors; Glutamic acid receptors; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - metabolism; HEK293 Cells; Hormone release; Humans; Hypothalamus; Kiss1 protein; Kisspeptins - pharmacology; Luteinizing hormone; Male; Males; Mice; Mice, Knockout; N-Methyl-D-aspartic acid receptors; Neurokinin; Neurokinin A; Neurokinin A - genetics; Neurokinin A - metabolism; Neurokinin B; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Nitric oxide; Nitric-oxide synthase; Puberty; Receptors; Regulators; Rodents; Senktide; Sexual Maturation - drug effects; Sexual Maturation - genetics; Signal Transduction - genetics; Signaling; Substance P
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2016-1807

The tachykinins substance P (SP) and neurokinin A (Tac1) have emerged as novel regulators of kisspeptin/GnRH release. Recently, we documented that SP modulates reproductive function in the female mouse. Here, we extended this characterization to the male mouse. Tac1−/− male mice showed delayed puberty onset. They also presented significantly decreased expression levels of Pdyn (dynorphin) and Nos1 (nitric oxide synthase) in the mediobasal hypothalamus and elevated Gnrh1 levels. Unexpectedly, the response of Tac1−/− mice to central kisspeptin or senktide (neurokinin B receptor–agonist) administration was significantly decreased compared with controls, despite the preserved ability of GnRH neurons to stimulate luteinizing hormone release as demonstrated by central N-methyl-D-aspartate receptor administration, suggesting a deficit at the GnRH neuron level. Importantly, we demonstrated that kisspeptin receptor and SP receptor (NK1R) heterodimerize, indicating that changes in the SP tone could alter the responsiveness of GnRH neurons to kisspeptin. Finally, electrophysiological recordings from arcuate Kiss1 neurons showed that, although virtually all Kiss1 neurons responded to NKB and senktide, only half responded to an NK1R agonist and none to the neurokinin A receptor agonist at a 1-μM dose. In summary, we provide compelling evidence for a role of Tac1 in the control of reproductive function in the male mouse, suggesting a predominant central action that may involve a change in the balance of neural factors that control GnRH expression.This work focuses on the role of Tac1 products (SP and NKA) on reproduction in male mice. Tac1 products are involved in puberty onset and facilitate full responsiveness of GnRH neurons to kisspeptin.