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to an apparent reduction in LH secretion. Excessive activation of NK3R might there-
fore cause dysfunction among the NKB/Dyn-kisspeptin-GnRH-LH cascade, such as
a hyperenhancement of the Dyn/KOR signaling tone, before the resumption of nor-
mal bursting activities of KNDy neurons. This may, at least in part, be responsible
for the inconsistent results of LH responses to pharmacological NK3R agonist treat-
ments [
40
,
53
,
57
,
92
].
Electrophysiological Properties of the GnRH Pulse Generator
Knobil and colleagues uncovered the single unit components of the MUA underly-
ing the operation of the GnRH pulse generator by cluster analysis in monkeys [
33
].
The results indicated that the MUA volley is the consequence of coincidental
increases in the fi ring rate of individual cells that are active even during the intervals
between volleys, rather than the activation of previously silent cells. Thus, neurons
consisting of the GnRH pulse generator appear to have electrophysiological proper-
ties for both spontaneous and burst activities. In this context, it is of great interest
that recent fi ndings in Kiss1-CreGFP mice [
121
] and genetically intact guinea pigs
[
122
] show that ARC kisspeptin neurons do possess such electrophysiological prop-
erties. Levine [
123
,
124
] has proposed in his model of the GnRH pulse-generating
mechanism that the random activity of any neurons within an interconnected net-
work would initiate the process of the pulse-generating activity. It is conceivable
that spontaneous activity in ARC kisspeptin neurons plays a role to generate such
random activity, though this requires further investigation.
A Putative Mechanism of the GnRH Pulse Generation
Taken all together, we propose, although highly speculative, the following working
hypothesis for the mechanism of GnRH pulse generation [
55
]:
1. KNDy neurons in the ARC send projections to GnRH terminals in the ME, while
their collaterals and/or dendrites form a bilateral neural network connecting each
other (Fig. 14.6a).
Fig. 14.6
(continued) inhibits the bursting activities. Progesterone enhances the inhibitory tone of
Dyn/KOR signaling, which acts to reduce the frequency of the periodic burst. Estrogen attenuates
the stimulatory tone of NKB/N3R signaling and the excitability of KNDy neurons, which act to
shorten the duration of each burst and to reduce the frequency of the periodic burst, respectively.
(
c
) A sustained activation of KNDy neurons by continuous administration of NK3R agonist results
in an apparent rise in the random activity, leading to an increase in the frequency of the burst. (
d
)
A sustained attenuation of KOR signaling by continuous administration of KOR antagonist also
produces an increase in the frequency of the burst. See text for details
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