Kisspeptin and GnRH Pulse Generation - Kisspeptin Signaling in Reproductive Biology - page 296

Anatomical evidence indicates that KNDy neurons comprise a neuronal network
interconnected by axon (and/or dendritic) collaterals. For example, in the rodent [ 63 ]
and ovine [ 63 ] ARC, NKB/Dyn neurons receive close appositions from fi bers contain-
ing NKB/Dyn. Dyn neurons in the ARC form synaptic contacts with Dyn fi bers [ 64 ].
It is therefore not surprising that kisspeptin/NKB and kisspeptin/Dyn neurons are sur-
rounded by their own dense network of fi bers [ 53 ]. Moreover, an anterograde tracer
study in rats revealed that NKB neurons in the ARC are bilaterally interconnected by
NKB axons [ 65 ]. Importantly, NKB neurons in the ARC contain NKB receptors
(NK3R) [ 63 , 66 ] and ARC Kiss1 neurons express both NK3R and KOR [ 57 ]. These
reports suggest that NKB/NK3R and Dyn/KOR signaling pathways might play a role
in an auto-feedback loop (or paracrine feedback loop) of KNDy neurons [ 55 , 57 , 62 ,
67 , 68 ]. However, it should be noted that one study recently reported that KNDy neu-
rons in the male mouse do not to express KOR [ 58 ], which is inconsistent with this
group's earlier report. Other KOR-expressing interneurons mediating Dyn's action
might be involved in the auto-feedback loop of KNDy neurons in the ARC.
NKB/NK3R signaling is thought to play a role in stimulating neuronal activity
[ 69 ], whereas Dyn/KOR (Dyn receptor) signaling is considered to participate in
suppressing neuronal activity [ 70 , 71 ]. By possessing these two opposing signaling
mechanisms and forming an anatomical network structure, the population of ARC
KNDy neurons seems to possess the required framework for a role as a GnRH pulse
generator. For example, reciprocal interactions between NKB/NK3R and Dyn/KOR
(or other inhibitory signaling mediating the Dyn action) signaling would make it
possible to generate pseudo-pacemaking activities, providing the oscillatory drive
of the GnRH pulse generator. The neural network would be suitable for electro-
physiological synchronization of individual neurons.
Kisspeptin fi bers make extensive associations with GnRH axons in the ME [ 72 -
75 ], and kisspeptin could therefore act as the output of the pulse generator to infl u-
ence GnRH neurons. Electron microscopy has revealed that kisspeptin axon
terminals are in fact in close apposition to GnRH axon terminals [ 73 , 74 ].
Considering the fact that NKB is contained in KNDy neurons, but not in POA
kisspeptin neurons (Fig. 14.3a-c ), and that a majority of those kisspeptin fi bers in
the ME also contain NKB (Fig. 14.3d-f ) [ 73 , 75 , 76 ], it is likely that KNDy neurons
send, although not exclusively, dense projections to the ME [ 62 , 68 ] and interact
with Kiss1r on GnRH axon terminals. However, the presence of Kiss1r protein on
GnRH axon fi bers has yet to be demonstrated since there is currently not a good
Kiss1r antibody.
It is thought that the GnRH pulse generator is responsive to the negative feedback
actions of gonadal steroids [ 77 ]. Although there are several populations of neurons
that contain sex steroid receptors in the hypothalamus, such as GABA [ 78 ], neuro-
peptide Y [ 79 ], substance P [ 80 ], somatostatin [ 81 ], beta-endorphin [ 82 ], or dopa-
mine [ 82 ] neurons, KNDy neurons are conspicuous in that virtually all of them
express both estrogen receptor alpha [ 63 , 83 - 86 ] and progesterone receptor [ 64 , 87 ]
in the female or androgen receptors in the male [ 88 ]. This anatomical property fur-
ther supports the possibility that the KNDy neurons may comprise for the GnRH
pulse generator.