Abstract:
BACKGROUND / AIMS : Kisspeptin is the major excitatory regulator
of gonadotropin-releasing hormone (GnRH) neurons and
is responsible for basal GnRH/LH release and the GnRH/LH
surge. Although it is widely assumed, based on mutations in
kisspeptin and Kiss1R, that kisspeptin acts to sustain basal
GnRH neuronal activity, there have been no studies to investigate
whether endogenous basal kisspeptin tone plays a direct
role in basal spontaneous GnRH neuronal excitability. It
is also of interest to examine possible interactions between
endogenous kisspeptin tone and other neuropeptides that
have direct effects on GnRH neurons, such as neuropeptide
Y (NPY) or cocaine- and amphetamine-regulated transcript
(CART), since the activity of all these neuropeptides changes
during states of negative energy balance. METHODS : Loose
cell-attached and whole-cell current patch-clamp recordings
were made from GnRH-GFP neurons in hypothalamic
slices from female and male rats. RESULTS : Kisspeptin activated
GnRH neurons in a concentration-dependent manner
with an EC 50 of 3.32 ± 0.02 n M . Surprisingly, a kisspeptin an-endogenous kisspeptin tone. Furthermore, inhibition of endogenous
kisspeptin tone blocked the direct activation of
GnRH cells that occurs in response to antagonism of NPY Y5
receptor or by CART. CONCLUSIONS : Our electrophysiology
studies suggest that basal endogenous kisspeptin tone is
not only essential for spontaneous GnRH neuronal firing, but
it is also required for the net excitatory effects of other neuropeptides,
such as CART or NPY antagonism, on GnRH neurons.
Therefore, endogenous kisspeptin tone could serve as
the linchpin in GnRH activation or inhibition.
