Kisspeptin and GnRH Pulse Generation - Kisspeptin Signaling in Reproductive Biology - page 304

2. The random activity of any neuron within the KNDy neuron network would
propagate among other neurons in the network through NKB/NK3 signaling to
evoke synchronized bursting activities (volleys of action potentials) among
KNDy neurons, which may function as a kind of positive feedback mechanism.
3. At the same time, Dyn would also be released by bursting activities in KNDy
neurons, and Dyn/KOR signaling is considered to act, with a slight time lag
(perhaps caused by differences of secretory mechanism or cellular signal trans-
duction processes between NKB/NK3R and Dyn/KOR signaling), to extinguish
these bursts, resulting in the net activity of the KNDy neuronal network to be an
episodic oscillation (Fig. 14.6b).
4. It is suggested that Dyn/KOR signaling then imposes a prolonged quiescence, or
a refractory period, which lasts until the drive of Dyn/KOR signaling diminishes
enough to allow the propagation of random activities again.
5. The reciprocal interaction between the stimulatory tone of NKB/NK3R signal-
ing and the inhibitory tone of Dyn/KOR signaling would generate intermittent
oscillations, providing a pseudo-pacemaking activity in the KNDy neuron net-
work (Fig. 14.6b ).
6. Each oscillation would induce a pulse of kisspeptin release at the ME, which in
turn would trigger a discharge of GnRH through kisspeptin/Kiss1r signaling,
producing a pulsatile mode of GnRH secretion into the portal circulation
(Fig. 14.6a ).
This hypothesis is in accord with that of other research laboratories who have
established the KNDy cell model [ 57 , 62 , 68 ] as well as the model proposed by
Levine [ 123 , 124 ] before the discovery of kisspeptin.
Implications Based on the Hypothesis
The Source of the MUA Volley (GnRH Pulse Generator Activity)
The MUA volleys, which represent electrophysiological manifestations of the
GnRH pulse generator, can be monitored at the posterior ARC (Fig. 14.1 ). Although
there are several neuronal populations, such as NPY [ 46 ], dopamine [ 82 ], substance
P [ 80 ], as well as other yet to be determined neurons in the ARC, the population of
KNDy neurons might be the only one that is fully equipped with the prerequisite
neural mechanisms to act as the GnRH pulse generator, i.e., generating rhythmic
oscillation, synchronizing activities within the population, and transmitting the
rhythmic activity to GnRH neurons. Moreover, the negative feedback action of E2
on LH secretion, which is mediated by the GnRH pulse generator [ 77 ], is com-
pletely diminished by a pharmacological ablation of KNDy neurons [ 125 ]. Thus, it
is plausible that the population of KNDy neurons is the intrinsic source of the MUA
volley observed at the posterior ARC in goats [ 53 , 54 ] as well as in the MBH of
monkeys [ 29 - 35 ], rats [ 36 - 40 ], and goats [ 41 - 46 ].