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fi de synaptic terminals [ 120 ]. More importantly, there is now direct EM evidence in
mice of axo-dendritic and axo-somatic contacts between kisspeptin fi bers and pre-
optic GnRH cells [ 106 ]. This compelling observation needs to be confi rmed in other
species, such as monkeys and sheep, where GnRH neurons examined at an EM level
are frequently surrounded and separated from nearby presynaptic terminals by
astroglial processes [ 121 , 122 ].
In addition to inputs at the level of GnRH cell bodies, there is also EM evi-
dence that direct membrane appositions exist between kisspeptin and GnRH ter-
minals within the median eminence. In rats, kisspeptin-positive terminals formed
direct membrane contacts with GnRH terminals, although these contacts were
seen in the internal zone of the median eminence [ 123 ]. Similarly, in the goat
[ 36 ], kisspeptin and GnRH terminals were seen to form direct axo-axonic con-
tacts; however these contacts were seen in the external zone, unlike those
observed in rats. In both species, axo-axonic contacts between kisspeptin and
GnRH terminals lacked typical synaptic morphological specializations (e.g., syn-
aptic densities, clefts) so that the mechanism of communication remains unclear.
Consistent with the fact that in most species, kisspeptin fi bers are sparse in the
external zone (Table 3.2 ), kisspeptin cells in mice are not labeled by peripheral
injections of tracers, indicating that they do not have access to fenestrated capil-
laries as GnRH cells do [ 108 ]. Thus, even given the presence of direct axo-axonic
connections, it seems likely that for kisspeptin to regulate GnRH release within
the median eminence, it must act via diffusion either to the external zone or
through actions on other local intermediaries (e.g., glial cells). However, there is
no evidence for the presence of Kiss1r in glial cells at this time.
While the precise origin of all kisspeptin inputs to GnRH cell bodies and terminals
has yet to be defi ned, using the techniques described above (“efferent projections”),
there is evidence that at least some of this input arises from both RP3V and ARC popula-
tions. In mice, dual-labeled kisspeptin/TH terminals arising from the RP3V population
innervate POA GnRH neurons (Fig. 3.2b ), although they represent less than 20% of all
kisspeptin contacts on those cells [ 64 ]. Recent work using galanin as a co-marker for
RP3V kisspeptin cells and NKB as a co-marker for ARC kisspeptin (KNDy) cells con-
fi rmed inputs to GnRH cell bodies from RP3V kisspeptin cells in mice, as well as show-
ing direct inputs from the ARC population in this species [ 106 ]. Once again, the
identifi ed inputs represented a small percentage of the total number of kisspeptin inputs
to GnRH neurons. In the sheep, kisspeptin terminals arising from the ARC contact
GnRH neurons in both the POA and MBH (where they are also located in this species)
(Fig. 3.2a ), and double-labeled KNDy terminals appear to account for the largest per-
centage of the total number of kisspeptin afferents. Finally, there is evidence in multiple
species that KNDy cells provide input to the median eminence (Table 3.2 ), and that at
least some of this input forms the close contacts observed with GnRH terminals, at least
in the internal zone. In rats and sheep, dynorphin fi bers of ARC origin (because they
co-localize NKB) innervate the median eminence [ 105 , 111 ], and dynorphin terminals
in the sheep make direct contacts with GnRH terminals at an EM level (Fig. 3.2c ). Thus,
the available evidence to date suggests that while both RP3V and ARC kisspeptin
populations contribute direct inputs to GnRH cell bodies, inputs at the level of GnRH
terminals in the median eminence arise from the ARC. We would note that these identi-
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