Neurobiological Mechanisms Underlying Kisspeptin Activation of Gonadotropin-releasing Hormone (GnRH) Neurons at Puberty

Studies undertaken in many species indicate that kisspeptin-Gpr54 signaling is essential for the activation of gonadotropin-releasing hormone (GnRH) neurons to bring about puberty. Investigations in transgenic mouse models, in particular, have highlighted the importance of kisspeptin signaling at the level of the GnRH neuron itself in this process. This review aims to highlight current understanding of the neurobiological mechanisms underlying the kisspeptin activation of postnatal GnRH neurons. The three key features of the kisspeptin-Gpr54-GnRH neuron axis leading up to puberty are (i) the expression of adult-like levels of Gpr54 mRNA in GnRH neurons well in advance of puberty, (ii) a modest increase in the electrical response of GnRH neurons to Gpr54 activation across postnatal development and (iii), the "sudden" appearance of kisspeptin fibers surrounding GnRH neuron cell bodies/proximal dendrites just prior to puberty onset. These kisspeptin fibers are likely to originate from the kisspeptin population located in the rostral periventricular region of the third ventricle (RP3V). Together, available data suggest that the key step in the kisspeptin control of puberty lies in the control of kisspeptin synthesis within RP3V kisspeptin neurons that innervate GnRH neurons. This has recently been shown to be dependent upon circulating estradiol concentrations. As such, we propose that RP3V kisspeptin neurons represent a critical estradiol-dependent amplification mechanism brought into play relatively late in pubertal development to activate GnRH neurons and complete the process of puberty onset. Subsequently, in the adult female, this same circuitry is used to activate GnRH neurons to generate the cyclical preovulatory GnRH/LH surge.