Kisspeptin Regulation of Neuronal Activity throughout the Central Nervous System

Xinhuai Liu,Allan E. Herbison 대한내분비학회 2016 Endocrinology and metabolism Vol.31 No.2

Kisspeptin signaling at the gonadotropin-releasing hormone (GnRH) neuron is now relatively well characterized and established as being critical for the neural control of fertility. However, kisspeptin fibers and the kisspeptin receptor (KISS1R) are detected throughout the brain suggesting that kisspeptin is involved in regulating the activity of multiple neuronal circuits. We provide here a review of kisspeptin actions on neuronal populations throughout the brain including the magnocellular oxytocin and vasopressin neurons, and cells within the arcuate nucleus, hippocampus, and amygdala. The actions of kisspeptin in these brain regions are compared to its effects upon GnRH neurons. Two major themes arise from this analysis. First, it is apparent that kisspeptin signaling through KISS1R at the GnRH neuron is a unique, extremely potent form or neurotransmission whereas kisspeptin actions through KISS1R in other brain regions exhibit neuromodulatory actions typical of other neuropeptides. Second, it is becoming increasingly likely that kisspeptin acts as a neuromodulator not only through KISS1R but also through other RFamide receptors such as the neuropeptide FF receptors (NPFFRs). We suggest likely locations of kisspeptin signaling through NPFFRs but note that only limited tools are presently available for examining kisspeptin cross-signaling within the RFamide family of neuropeptides.

Serotonin acts through 5-HT1 and 5-HT2 receptors to exert biphasic actions on GnRH neuron excitability in the mouse.

Bhattarai, Janardhan P,Roa, Juan,Herbison, Allan E,Han, Seong Kyu The Endocrine Society 2014 Endocrinology Vol.155 No.2

<P>The effect of serotonin (5-HT) on the electrical excitability of GnRH neurons was examined using gramicidin perforated-patch electrophysiology in transgenic GnRH-green fluorescent protein mice. In diestrous female, the predominant effect of 5-HT was inhibition (70%) with 50% of these cells also exhibiting a late-onset excitation. Responses were dose dependent (EC(50) = 1.2μM) and persisted in the presence of amino acid receptor antagonists and tetrodotoxin, indicating a predominant postsynaptic action of 5-HT. Studies in neonatal, juvenile, peripubertal, and adult mice revealed that 5-HT exerted less potent responses from GnRH neurons with advancing postnatal age in both sexes. In adult male mice, 5-HT exerted less potent hyperpolarizing responses with more excitations compared with females. In addition, adult proestrous female GnRH neurons exhibited reduced inhibition and a complete absence of biphasic hyperpolarization-excitation responses. Studies using 5-HT receptor antagonists demonstrated that the activation of 5-HT(1A) receptors mediated the inhibitory responses, whereas the excitation was mediated by the activation of 5-HT(2A) receptors. The 5-HT-mediated hyperpolarization involved both potassium channels and adenylate cyclase activation, whereas the 5-HT excitation was dependent on protein kinase C. The effects of exogenous 5-HT were replicated using fluoxetine, which enhances endogenous 5-HT levels. These studies demonstrate that 5-HT exerts a biphasic action on most GnRH neurons whereby a fast 5HT(1A)-mediated inhibition occurs alongside a slow 5-HT(2A) excitation. The balance of 5-HT-evoked inhibition vs excitation is developmentally regulated, sexually differentiated, and variable across the estrous cycle and may play a role in regulation of hypothalamic-pituitary-gonadal axis throughout postnatal development.</P>

Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty

Clarkson, J.,Han, S.K.,Liu, X.,Lee, K.,Herbison, A.E. North-Holland 2010 Molecular and cellular endocrinology Vol.324 No.1

Studies undertaken in many species indicate that kisspeptin-Gpr54 signaling is essential for the activation of gonadotropin-releasing hormone (GnRH) neurons to bring about puberty. Investigations in transgenic mouse models, in particular, have highlighted the importance of kisspeptin signaling at the level of the GnRH neuron itself in this process. This review aims to highlight current understanding of the neurobiological mechanisms underlying the kisspeptin activation of postnatal GnRH neurons. The three key features of the kisspeptin-Gpr54-GnRH neuron axis leading up to puberty are (i) the expression of adult-like levels of Gpr54 mRNA in GnRH neurons well in advance of puberty, (ii) a modest increase in the electrical response of GnRH neurons to Gpr54 activation across postnatal development and (iii), the ''sudden'' appearance of kisspeptin fibers surrounding GnRH neuron cell bodies/proximal dendrites just prior to puberty onset. These kisspeptin fibers are likely to originate from the kisspeptin population located in the rostral periventricular region of the third ventricle (RP3V). Together, available data suggest that the key step in the kisspeptin control of puberty lies in the control of kisspeptin synthesis within RP3V kisspeptin neurons that innervate GnRH neurons. This has recently been shown to be dependent upon circulating estradiol concentrations. As such, we propose that RP3V kisspeptin neurons represent a critical estradiol-dependent amplification mechanism brought into play relatively late in pubertal development to activate GnRH neurons and complete the process of puberty onset. Subsequently, in the adult female, this same circuitry is used to activate GnRH neurons to generate the cyclical preovulatory GnRH/LH surge.

Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons.

Campbell, Rebecca E,Gaidamaka, Galina,Han, Seong-Kyu,Herbison, Allan E National Academy of Sciences 2009 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.106 No.26

<P>The pulsatile release of gonadotropin-releasing hormone (GnRH) is critical for mammalian fertility, but the mechanisms underlying the synchronization of GnRH neurons are unknown. In the present study, the full extent of the GnRH neuron dendritic tree was visualized by patching and filling individual GnRH neurons with biocytin in acute brain slices from adult GnRH-green fluorescent protein (GFP) transgenic mice. Confocal analysis of 42 filled GnRH neurons from male and female adult mice revealed that the dendrites of the great majority of GnRH neurons (86%) formed multiple close appositions with dendrites of other GnRH neurons. Two types of interactions were encountered; the predominant interaction was one of vertical dendritic bundling where dendrites were found to wrap around each other in the same axis. The other interaction was one in which a GnRH neuron dendrite intercepted other GnRH neuron dendrites in a perpendicular fashion. Electron microscopy using pre-embedded, silver-enhanced immunogold labeling for both GnRH and GFP peptides in GnRH-GFP transgenic mice, confirmed that GnRH neuron dendrites were often immediately juxtaposed. Membrane specializations, including punctae and zonula adherens, were found connecting adjacent dendritic elements of GnRH neurons. Remarkably, individual afferent axon terminals were found to synapse with multiple GnRH neuron dendrites at sites of bundling. Together, these data demonstrate that GnRH neurons are not isolated from one another but, rather, interconnected via their long dendritic extensions. The observation of shared synaptic input to bundled GnRH neuron dendrites suggests a mechanism of GnRH neuron synchronization.</P>

Gonadotrophin-Releasing Hormone (GnRH) Exerts Stimulatory Effects on GnRH Neurones in Intact Adult Male and Female Mice

Han, S.-K.,Lee, K.,Bhattarai, J. P.,Herbison, A. E. Blackwell Publishing Ltd 2010 Journal of neuroendocrinology Vol.22 No.3

<P>There is substantial evidence for a role of the neuropeptide gonadotrophin-releasing hormone (GnRH) in the regulation of GnRH neurone secretion but how this is achieved is not understood. We examined here the effects of GnRH on the electrical excitability and intracellular calcium concentration ([Ca<SUP>2+</SUP>]<SUB>i</SUB>) of GnRH neurones in intact adult male and female mice. Perforated-patch electrophysiological recordings from GnRH-green fluorescent protein-tagged GnRH neurones revealed that 3 n<SMALL>M</SMALL>–3 &mgr;<SMALL>M</SMALL> GnRH evoked gradual approximately 3 mV depolarisations in membrane potential from up to 50% of GnRH neurones in male and female mice. The depolarising effect of GnRH was observed on approximately 50% of GnRH neurones throughout the oestrous cycle. However, at pro-oestrus alone, GnRH was also found to transiently hyperpolarise approximately 30% of GnRH neurones. Both hyperpolarising and depolarising responses were maintained in the presence of tetrodotoxin. Calcium imaging studies undertaken in transgenic GnRH-pericam mice showed that GnRH suppressed [Ca<SUP>2+</SUP>]<SUB>i</SUB> in approximately 50% of GnRH neurones in dioestrous and oestrous mice. At pro-oestrus, 25% of GnRH neurones exhibited a suppressive [Ca<SUP>2+</SUP>]<SUB>i</SUB> response to GnRH, whereas 17% were stimulated. These results demonstrate that n<SMALL>M</SMALL> to &mgr;<SMALL>M</SMALL> concentrations of GnRH exert depolarising actions on approximately 50% of GnRH neurones in males and females throughout the oestrous cycle. This is associated with a reduction in [Ca<SUP>2+</SUP>]<SUB>i</SUB>. At pro-oestrus, however, a further population of GnRH neurones exhibit a hyperpolarising response to GnRH. Taken together, these studies indicate that GnRH acts predominantly as a neuromodulator at the level of the GnRH cell bodies to exert a predominant excitatory influence upon GnRH neurones in intact adult male and female mice.</P>

Somatostatin Inhibition of Gonadotropin-Releasing Hormone Neurons in Female and Male Mice

Bhattarai, Janardhan P.,Kaszá,s, Attila,Park, Seon Ah,Yin, Hua,Park, Soo Joung,Herbison, Allan E.,Han, Seong Kyu,Á,brahá,m, Istvá,n M. The Endocrine Society 2010 Endocrinology Vol.151 No.7