Interactions Between Kisspeptins and Neurokinin B - Kisspeptin Signaling in Reproductive Biology - page 326

blunted LH responses due to NK3R desensitization still respond to kisspeptin;
however, monkeys subjected to Kiss1r desensitization showed a signifi cant reduc-
tion in their response to senktide treatment [ 31 , 83 ], although, admittedly, they did
present a marginal (perhaps kisspeptin-independent) stimulation of LH release.
On the whole, these data strongly suggest a putative action of NKB upon ARC
Kiss1 neurons; however, at the same time, we cannot rule out any additional action
of this peptide on other brain areas or even different neuronal populations within the
ARC. Along these lines, several studies document the expression of NK3R in GnRH
terminals of rats [ 25 , 29 ] and Tacr3 mRNA in GnRH neurons in the mouse [ 87 ] as
well as in the immortalized GT1-7 cell line—a model of differentiated GnRH neu-
rons—[ 88 ]; however, a call of caution should be added since immortalized cell lines
do not always resemble in vivo models. Despite the latter observations, recent stud-
ies document the absence of NK3R immuno-localization and Tacr3 mRNA in
GnRH neurons of sheep [ 42 ] and mice [ 59 ], respectively, adding further contro-
versy to the role of NKB in the control of GnRH secretion. Indeed, mounting evi-
dence seems to further support the contention that GnRH neurons are devoid—or
only present marginal expression—of NK3R and therefore should not be consid-
ered as the primary site of action of NKB to regulate GnRH release. For example,
GnRH neurons coupled to green fl uorescent protein (GnRH-GFP) and subjected to
whole-cell recordings do not display signs of activation after senktide treatment in
the mouse [ 59 ]. This latter study, nonetheless, shows lack of activity at the level of
the GnRH cell body, but does not rule out the presence of NK3R at the level of
GnRH terminals. In this sense, Corander and colleagues demonstrated that, unlike
kisspeptin [ 89 ], addition of NKB to hypothalamic explants from male rats (devoid
of GnRH cell bodies) did not evoke any effect on GnRH release, which, initially,
would preclude any direct action at the level of these GnRH fi ber terminals [ 84 ].
The Roles of NKB/Kisspeptin Interactions in the Control
of Reproductive Function
Generation of GnRH Pulses
Although this topic includes a specifi c chapter devoted to this topic, it is, however,
worth highlighting the potential implications for reproductive physiology that
interactions of NKB and kisspeptin (and dynorphin) may have for the normal func-
tioning of the gonadotropic axis. There is convincing evidence to conclude that
kisspeptin release is pulsatile and that those pulses correlate with GnRH/LH pulses,
based on studies in monkeys and goats [ 76 , 90 , 91 ]. Consequently, we have proposed
a model whereby NKB from KNDy neurons acts autosynaptically on the NK3R of
the same neuron, through recurrent collaterals, as well as on other neighboring
KNDy neurons (Fig. 15.4 ) [ 56 , 76 , 92 , 93 ]. This action of NKB would evoke a syn-
chronized release of kisspeptin within the ARC, a fact of critical importance in order