Abstract
Kisspeptin (product of the kiss1 gene) is the most potent known activator of the hypothalamo-pituitary-gonadal axis. Both kiss1 and the kisspeptin receptor are highly expressed in the hypothalamus of vertebrates, and low doses of kisspeptin have a robust and long-lasting stimulatory effect on the rate of action potential firing of hypophysiotropic gonadotropin releasing hormone-1 (GnRH1) neurons in mice. Fish have multiple populations of GnRH neurons distinguished by their location in the brain and the GnRH gene that they express. GnRH3 neurons located in the terminal nerve (TN) associated with the olfactory bulb are neuromodulatory and do not play a direct role in regulating pituitary-gonadal function. In medaka fish, the electrical activity of TN-GnRH3 neurons is modulated by visual cues from conspecifics, and is thought to act as a transmitter of information from the external environment to the central nervous system. TN-GnRH3 neurons also play a role in sexual motivation and arousal states, making them an important population of neurons to study for understanding coordination of complex behaviors. We investigated the role of kisspeptin in regulating electrical activity of TN-GnRH3 neurons in adult medaka. Using electrophysiology in an intact brain preparation, we show that a relatively brief treatment with 100 nM of kisspeptin had a long-lasting stimulatory effect on the electrical activity of an extrahypothalamic population of GnRH neurons. Dose-response analysis suggests a relatively narrow activational range of this neuropeptide. Further, blocking action potential firing with tetrodotoxin and blocking synaptic transmission with a low Ca2+/high Mg2+ solution inhibited the stimulatory action of kisspeptin on electrical activity, indicating that kisspeptin is acting indirectly through synaptic regulation to excite TN-GnRH3 neurons. Our findings provide a new perspective on kisspeptin's broader functions within the central nervous system, through its regulation of an extrahypothalamic population of GnRH neurons involved in multiple neuromodulatory functions.
Highlights
Kisspeptin and its receptor (GPR54 or kiss1r) play major roles in the central regulation of the hypothalamo-pituitary-gonadal axis of vertebrates [1,2,3,4]
The stimulatory response was long lasting and was not eliminated during the washout period, similar to what was reported with murine hypothalamic/preoptic area (POA) gonadotropin releasing hormone-1 (GnRH1) neurons [8] [10]
A control group was included in this study in which neurons were continuously treated with 0 nM kiss1(10) (‘baseline’ saline solution) for 30 min, with no significant change in spike frequency. This indicates that the prolonged increase in electrical excitation in the experimental group was due to long-lasting stimulatory actions of kiss1(10), and not due to deterioration of the recording conditions leading to non-specific membrane depolarization
Summary
Kisspeptin (a product of the kiss gene) and its receptor (GPR54 or kiss1r) play major roles in the central regulation of the hypothalamo-pituitary-gonadal axis of vertebrates [1,2,3,4]. Studies investigating central actions of kisspeptin on reproduction have focused primarily on mammalian species, showing that it has potent stimulatory effects on GnRH/gonadotropin secretion and electrophysiological activity of GnRH1 neurons in the hypothalamus and preoptic area (POA) [8,9,10,11]. Studies in multiple species of fish have consistently shown that kiss is a more potent stimulator of central activation of gonadotropin secretion than kiss1 [13] [15] This suggests that kiss is the primary regulator of the hypothalamo-pituitary-gonadal axis in fish, while kiss might act as a weaker modulator of the reproductive axis and have other physiological roles in the brain. This latest finding suggests that kiss neurons are primarily involved in estrogen feedback and reproduction in medaka, throwing into question the relative roles of the different forms of kisspeptin in regulating reproduction
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