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. Author manuscript; available in PMC: 2013 Feb 13.
Published in final edited form as: J Neuroendocrinol. 2012 Jan;24(1):122–130. doi: 10.1111/j.1365-2826.2011.02160.x

17β-Oestradiol Regulation of Gonadotrophin-Releasing Hormone Neuronal Excitability

O K Rønnekleiv *,†, M A Bosch *, C Zhang *
PMCID: PMC3572201  NIHMSID: NIHMS434343  PMID: 21592235

Abstract

17β-Oestradiol (E2) is essential for cyclical gonadotrophin-releasing hormone (GnRH) neuronal activity and secretion. In particular, E2 increases the excitability of GnRH neurones during the afternoon of pro-oestrus in the rodent, which is associated with increased synthesis and secretion of GnRH. It is well established that E2 regulates the activity of GnRH neurones through both presynaptic and postsynaptic mechanisms. E2 significantly modulates the mRNA expression of numerous ion channels in GnRH neurones and alters the associated endogenous conductances, including potassium (KATP, A-type) currents and low-voltage T-type and high-voltage L-type calcium currents. Notably, KATP channels are critical for maintaining GnRH neurones in a hyperpolarised state for recruiting the T-type calcium channels, which are important for burst firing in GnRH neurones. In addition, there are other critical channels contributing to burst firing pattern, including the small conductance Ca2+-activated K+ channels that may be modulated by E2. Despite these advances, the cellular mechanisms underlying the cyclical GnRH neuronal activity and GnRH release are largely unknown. Ultimately, the ensemble of both pre- and post-synaptic targets of the actions of E2 will dictate the excitability and activity pattern of GnRH neurones.

Keywords: gonadotrophin-releasing hormone neurones, hyperpolarisation, T-type calcium channels, burst firing

Introduction

Gonadotrophin-releasing hormone (GnRH) neurosecretion and the control of the ovulatory cycle in females are modulated by gonadal steroids secreted from the ovaries. In addition, there is evidence for a role of locally (hypothalamic) synthesised steroids in the positive-feedback regulation of the luteinising hormone (LH) surge (1, 2). It has been found in a number of species, including the rat, sheep and rhesus monkey, that the preovulatory LH surge is accompanied by a surge in GnRH (3–6). The detailed relation between LH and GnRH has been most extensively evaluated in the sheep because, in this animal model, both portal and peripheral blood can be sampled simultaneously from awake freely moving animals, thus avoiding the stress of anaesthesia, restraint or the placement concerns associated with sampling from the arcuate nucleus/median eminence region (7, 8). During the luteal phase in the sheep, GnRH is secreted as low-frequency pulses, which change to high-frequency low-amplitude pulses during the mid-follicular phase (9). In comparison, the LH surge during the late-follicular phase (proestrus) is accompanied by a high amplitude GnRH surge (4, 10). Interestingly, in the sheep but not in the macaque or rat, the GnRH surge continues long after the LH surge has terminated (4, 6, 9), indicating that the gonadotrophs desensitise to the GnRH surge input in sheep, thus shutting off LH secretion before feedback inhibition of GnRH secretion. In ovariectomised females, the GnRH and accompanying LH pulse size are increased and pulse frequency decreased to approximately one every hour. 17β-Oestradiol (E2) treatment significantly reduces the GnRH and LH pulse size but increases pulse frequency, leading to an overall reduction in GnRH and LH secretion before induction of the GnRH and LH surge (7, 11). Collectively, these findings would indicate there are fundamental changes in GnRH neuronal firing activity during the different stages of the ovulatory cycle that are responsible for these changes. Consequently, in ovariectomised animals treated with E2 to mimic negative- and positive-feedback regulation of GnRH, one would predict robust differences in neuronal firing activity between the different stages. However, notwithstanding recent advances on cellular experimentation, we still do not understand all of the signalling mechanism(s) by which E2 regulates GnRH neurones. This review addresses current knowledge on E2 regulation of mRNA expression, signalling properties and excitability in GnRH neurones, comparing changes associated with E2-induced negative- and positive-feedback regulation of GnRH neurones.

GnRH neuronal activity during negative- and positive-feedback

Using cell attached single-unit extracellular recording to evaluate GnRH neuronal firing activities during negative- compared to positive- feedback, it has been shown that the GnRH neuronal firing rate is low during the morning negative-feedback period and significantly higher during the evening positive-feedback period (12). As a potential mechanism, the investigators explored the spontaneous GABAergic postsynaptic currents, which were increased during positive-feedback and decreased during negative-feedback (13). This is congruent with the idea that GABA acting at GABAA receptors is excitatory in GnRH neurones (14). The timing of the GnRH (LH) surge, and thus the increased activity of GnRH neurones at the time of the surge, is not only E2-dependent, but also it is entrained to a circadian input from the suprachiasmatic nucleus (SCN) (12, 15–17). The SCN expresses not only GABA and glutamate, but also vasopressin (VP) and vasoactive intestinal peptide (VIP) (18), which have received much attention as possible mediators of SCN circadian input to GnRH neurones and involvement in the timing of the GnRH surge (19–22). VP neurones within the SCN may act indirectly via kisspeptin neurones in the anteroventral periventricular nucleus (AVPV) area, but SCN VIP-projections may have a direct effect on GnRH neurones (16, 22, 23). VIP, when applied to GnRH neurones to test for alteration of firing rate in a cell attached mode, caused increased firing at surge onset in subpopulations of GnRH neurones, and had no effect on cell activity during morning negative-feedback (16). This supports the idea of a direct SCN input to GnRH neurones; however, further studies are necessary to more fully elucidate the SCN VIP functional input to GnRH neurones. Concerning the role of VP, anatomical studies support direct VP fibres from the SCN to the AVPV, and VP receptors are expressed on AVPV kisspeptin neurones (21). However, exogenous VP appears not to alter neuronal firing in the AVPV, questioning the physiological role of VP (24). Again, further experiments are needed to fully evaluate the SCN– AVPV–GnRH functional connection.

Models for GnRH neuronal firing

Studies in enhanced green fluorescent protein (EGFP)-GnRH mice have illustrated that GnRH neurones often fire in episodes of repetitive bursts (25–27). Currently, it is not known how the bursts are generated in GnRH neurones, although depolarising afterpotentials (also called afterdepolarising potentials) are proposed to be involved (27, 28). On the basis of current clamp and voltage clamp recordings in neurosecretory hypothalamic neurones, models have been developed including an ensemble of channels that appear to be critical for burst firing in parvocellular neurosecretory neurones (29–32). A recent model designed to explain short burst firing and related calcium oscillations in GnRH neurones has predicted that GnRH neurones spike spontaneously, which initiates the burst firing process by allowing an influx of a few Ca2+ ions. This is proposed to stimulate calcium-induced calcium release (CICR) from inositol- 1,4,5-trisphosphate (IP3) receptors, which is responsible for a large [Ca2+] transient. The calcium transient activates the slow afterhyperpolarisation small conductance (SK) current (sIAHP-SK), which arrests the firing. In addition, CICR turns on a much slower K+ channel, which is active for a much longer time and determines the interburst interval (31, 32).

On the basis of a model similar to that described and validated for thalamocortical relay neurones and hypothalamic neurosecretory neurones (29, 33–35), we had predicted that the T-type calcium current together with the hyperpolarisation-activated cation current (Ih) are essential for induction of burst firing in GnRH neurones and that calcium-dependent SK-type channels (underlying an AHP) are crucial for afterhyperpolarisation, allowing repetitive cycles of burst firing (29, 30).

E2 regulation of low threshold spikes (LTS) and T-type channels in GnRH neurones

We became interested in LTS and burst firing after discovering that LTS were prominent in arcuate nucleus dopamine neurones from E2-treated females (36). Later, it was determined that T-type calcium channels were responsible for the LTS (33, 37). Three subunits of the T-type channel (Cav3.1, Cav3.2, Cav3.3) have been cloned (38, 39), with the specific gating properties of the T-type channel being dependent on the subunit composition. Thus, the Cav3.1 and Cav3.2 current profiles are more similar compared to Cav3.3, and compelling evidence suggests that these subunits are involved in short burst firing in thalamocortical relay neurones (34).

Initially, we found that there was an E2-induced augmentation in gene expression of a Ca2+ channel (Cav3.1) subunit in the arcuate nucleus after 24 h of treatment (40) and after long-term E2 treatment (30 days) (41). The E2-induced increase in Cav3.1 subunit expression was accompanied by an increase in peak T-type Ca2+ current in arcuate neurones, including dopamine and POMC neurones (40), and in unidentified neurones in the VMH (42). On the basis of the role of T-type Ca2+ channels in modulating neuronal excitability (35, 43), the augmentation in the T-type Ca2+ current would facilitate burst firing and increase neurotransmitter release. Furthermore, the increase in Cav3.1 expression in the arcuate nucleus from E2 treatment did not occur in oestrogen receptor (ER) α knockout mice (44), indicating that the expression is dependent on the nuclear receptor or signalling molecule(s) induced by ERα during development. Importantly, a ligand for a putative membrane ER (mER) called STX, with no binding affinity to ERα or ERβ (45, 46), also significantly up-regulated the Cav3.1 subunit in the arcuate nucleus after long-term treatment (41). Collectively, this would suggest that the putative mER- and ERα-mediated transcriptional effects converge at the Cav3.1 gene.

GnRH neurones express all three of the T-type calcium channel subunits (Fig. 1) and the expression of these subunits are regulated by E2 in a subunit-specific and diurnal manner (Fig. 2) (47, 48). Interestingly, the mRNA expression of all three subunits are increased by E2 already in the morning (negative-feedback), and Cav3.3 remains elevated during the afternoon/evening (positive-feedback). These findings would indicate that the mRNA expression of the three Cav3 subunits is increased with increasing plasma E2 concentration but, during the afternoon (at the time of lights out), a yet unidentified circadian signal shuts off the mRNA production of Cav3.1 and Cav3.2, but not Cav3.3. Of importance is the fact that T-type calcium currents can be measured in the majority of GnRH neurones (47, 49), and the V1/2 for T-channel de-inactivation is −80.4 mV (i.e. the potential at which half of the T-type calcium channels are recruited as measured during the morning) (47). Complementing the mRNA data, T-type current density is also increased with E2 treatment already in the morning and remains elevated in the afternoon/evening together with increased rebound excitation (47). The role of the T-type Ca2+ currents, as found in other neuronal systems, is to facilitate rhythmic intracellular Ca2+ transients by initiating membrane depolarisation that recruits high voltage-activated (HVA) Ca2+ currents (50, 51). This is of functional significance because HVA Ca2+ currents are prevalent in GnRH neurones but they can only be recruited from a more depolarised (−40mV) state (52); whereas, low voltage-activated T-type currents are recruited from a more hyperpolarised state (Fig. 3) (i.e. they provide the link for setting off burst firing as indicated from subunit deletion studies) (33, 47–49, 52–54). Importantly, the T-type channel subunit expression, current density and rebound excitation of GnRH neurones are significantly enhanced with a surge-inducing E2-treatment paradigm (47). Therefore, the E2-dependent increase in T-type calcium channels may serve to augment the excitability of GnRH neurones in preparation for the GnRH (LH) surge. However, further studies are needed for a more complete understanding of the role of T-type channels in GnRH neurones. Not unexpectedly, L-type calcium currents are also regulated by E2 in GnRH neurones (52). In ovariectomised mice given an E2 treatment to induce afternoon LH surges, the peak L-type current was reduced during the morning at the time of negative-feedback but increased during the afternoon at the time of positive-feedback. This would indicate that L-type currents may be significant contributors to the afternoon surge of GnRH (LH). However, the diurnal signal that precisely activates this current is unknown and needs to be further investigated.

Fig. 1.

Fig. 1

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CaV3.1, CaV3.2, and CaV3.3 mRNA expression in single gonadotrophin- releasing hormone (GnRH) neurones. (A) Representative gel illustrating the mRNA expression of CaV3.1, CaV3.2, and CaV3.3 subunits in harvested GnRH neurones from 17β-oestradiol (E2)-treated animals. The expected size of the polymerase chain reaction products are (in base pairs): for GnRH, 239 bp; for CaV3.1, 250 bp; for CaV3.2, 284 bp; for CaV3.3, 128 bp. Control GnRH neurone (-RT) was amplified from a harvested cell without reverse transcriptase. (A total of eight neurones were processed without RT, all of which were negative) MM, Molecular marker. (B) Summary bar graphs of the percentages of expression of CaV3.1, CaV3.2, and CaV3.3 in GnRH neurones from oil- or E2-treated animals. Twelve to 20 GnRH neurones from each of four or five E2-treated and 12–20 neurones from each of four oil-treated females were analysed, and the mean number of neurones expressing CaV3 subunits from each animal was used for further analysis. Bar graphs represent the mean ± SEM of percentage GnRH neurones expressing each CaV3 subunit/animal. Numbers of animals are indicated Reproduced with permission from Zhang et al. (47).

Fig. 2.

Fig. 2

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17β-Oestradiol (E2) regulates CaV3.1, CaV3.2 and CaV3.3 mRNA expression in gonadotrophin-releasing hormone (GnRH) neurones. (A, B) Quantitative real-time polymerase chain reaction measurements of CaV3.1, CaV3.2 and CaV3.3 mRNAs in GnRH neuronal pools (3–5 per animal) from oil- and E2-treated mice (n = 3–6 animals per group) obtained during the morning (A) or during the afternoon (B). E2 upregulates the mRNA expression of CaV 3.1, CaV3.2, and CaV3.3 during the morning. CaV3.3 remained high during the afternoon but CaV3.1 and CaV3.2 were down-regulated. The expression values were calculated via the ΔΔCT method and normalised to the mean ΔCT of the oil-treated samples. Bar graphs represent the mean ± SEM. *P < 0.05, oil versus E2. Reproduced with permission from Zhang et al. (47).

Fig. 3.

Fig. 3

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17β-Oestradiol (E2) enhances T-type Ca2+ channel-induced low threshold spikes (LTS) in gonadotrophin-releasing hormone (GnRH) neurones. (A) A silent GnRH neurones was induced to fire from its resting membrane potential (−57 mV) with a depolarising current pulse. Note the regular firing (action potentials) in this representative GnRH neurone. (B, C) Representative evening recordings from GnRH neurones in E2- (B) and oil-treated (C) females showing hyperpolarisation-induced burst firing. There was no spontaneous firing at the resting membrane potentials; however, a hyperpolarisating current pulse to −83 mV for 1 s with a quick return to their resting membrane potential induced rebound excitation with four versus one fast sodium spikes riding on the LTS in a GnRH neurone from E2 and oil-treated females, respectively. Cells were recorded in K+-gluconate internal solution with 11 mM ethylene glycol-bis(2-aminoethylether)- N,N,N′,N′-tetraacetic acid (EGTA) and 100 μM 2-aminoethyl diphenylborinate (2-APB) added to the normal artificial cerebrospinal fluid to block the A-type potassium channel (91). (D, E) In another cell from an E2-treated female, T-type calcium channel-mediated calcium spikes (superimposed traces of rebound depolarisation) were clearly displayed in the presence of tetrodotoxin (D), and the LTS were blocked by nickel (200 μM) (D). The bottom trace shows the current-clamp protocol for (D) and (E). Note the minor activation of Ih, supporting findings that T-type channels underlie the LTS in GnRH neurones. The LTS serves to bring the membrane potential to threshold for fast sodium spike generation, which is the most efficient mode for transmitter (neuropeptide) release not only in GnRH neurones, but also neurones throughout the central nervous system.

Hyperpolarising input to GnRH neurones

It is well known that Kir channels are critical for maintaining excitable cells in a hyperpolarised resting state closer to EK but, once cells are depolarised, the channels allow for the quick transition to long depolarising responses because of their inwardly rectifying properties (55). Accordingly, with greater membrane hyperpolarisation of GnRH neurones, there is an increase in the number of Na+ spikes during rebound excitation (Fig. 3) (47). Indeed, KATP and G protein-coupled inwardly-rectifying potassium (GIRK) channels appear to be the critical Kir channels in GnRH neurones for maintaining the membrane in a relatively negative resting state (56, 57). Blocking KATP channels with the sulphonylurea tolbutamide significantly depolarises GnRH neurones, which is indicative of tonic KATP channel activity that is significantly augmented with E2 treatment (56). We also know that GABAergic, opioid, neuropeptide Y and perhaps melanin-concentrating hormone (MCH) input via their respective GABAB, μ-opioid, Y5 and MCH1 receptors activate GIRK channels to hyperpolarise GnRH neurones (57–60). This combination of inputs, leading to membrane hyperpolarisation, would allow for the recruitment of multiple excitatory conductances that are critical for generating burst firing in central nervous system neurones (29, 30, 35, 43).

Importantly, GnRH neurones express a time-dependent, hyperpolarisation- activated, cation current (Ih or pacemaker current) that contributes to rhythmic burst firing (30, 56, 58, 61). The activation of Ih by hyperpolarisation increases the spike frequency (61). In addition, the inhibition of Ih alters the pattern of burst firing and reduces the slope of recovery from the afterhyperpolarisation, supporting the idea that Ih plays an important role in GnRH neuronal excitability and contributes to burst firing.

Neuronal excitability and frequency of firing are also determined by the AHP that follows an action potential, and SK channels underlie a component of the median afterhyperpolarisation (mAHP) K+ currents in CA1 pyramidal cells and other neurones (62). SK channel subunits are expressed in GnRH neurones (63, 64), and SK channel activation exerts a powerful influence on firing properties of GnRH neurones. However, recent findings have demonstrated at least two components of the slow IAHP in GnRH neurones; one that is relatively fast and sensitive to apamin (SK) and a different slow-onset yet uncharacterised current that is sensitive to UCL2077 (31). The former regulates both intraburst and interburst neuronal firing, whereas the latter regulates only the interburst activity. Thus, multiple K+ channels may play a key role in modulating GnRH neuronal excitability and the firing pattern during different reproductive states (31, 64, 65).

Intracellular calcium oscillation in GnRH neurones

Experiments in vitro using perifused hypothalamic tissue, primary hypothalamic cultures or a GT1 GnRH neuronal cell line have revealed that pulsatile GnRH release is present in vitro (66, 67). The spontaneous pulsatility in GnRH release from neuronal cultures is abolished in Ca2+-deficient medium and is attenuated in the presence of nifedipine, an antagonist of L-type voltage-sensitive Ca2+ channels (67), emphasising the importance of calcium ions, calcium (L-type) channels and / or other calcium-dependent mechanisms for GnRH pulsatility.

More recently, a series of studies have shown that, in mouse hypothalamic neuronal explants and in primate nasal placode cultures, E2 augments synchronous intracellular Ca2+ oscillations in developing GnRH neurones (68–70). This relatively rapid effect is observed within 10–30 min of the application of E2, implicating novel ERs or novel actions of classical ERs as mediators of the action of E2 in GnRH neurones. The calcium oscillations in the presence of TTX are most likely the result of E2 acting directly on GnRH neurones. Furthermore, E2 conjugated to bovine serum abumin (BSA) at the C-17 position (E2-17 BSA) or to a large nondegradable poly(amido)amine-dendrimer macromolecule (71) mimics the effects of E2 on intracellular calcium oscillations (68–70). However, in mouse explant experiments (68, 69), the E2-induced calcium oscillations are blocked by ICI 182,780 suggesting that an ER is involved. By contrast, E2-induced calcium oscillations in the primate placode cultures are not blocked by the antagonist ICI 182,780, and ICI 182,780 alone has no effect, suggesting that a non-ER mediated mechanism may be involved in E2 regulation of calcium oscillations in primate GnRH neuronal cultures (70, 72). The actions of E2-BSA in mouse and monkey GnRH neuronal cultures are abrogated by pertussis toxin treatment, supporting a role for a G protein-coupled membrane receptor (68, 69, 72). Interestingly, GPR30 is expressed in developing primate GnRH neurones and may be responsible, in part, for the rapid actions of E2 in these neurones (72). Calcium oscillations in GnRH neurones can also be induced presynaptically via an ERα-dependent release of GABA from presynaptic terminals (73). Collectively, these findings indicate that there are multiple acute actions of E2 in GnRH neurones, some of which may involve a novel receptor and perhaps GPR30, and some that involve ERα and / or ERβ.

To study calcium oscillations in adult GnRH neurones, slices from genetically-modified mice that express the calcium indicator ratiometric pericam in GnRH neurones have been utilised (74). With this model, dual recordings of calcium transients and electrical activity revealed that intracellular calcium transients, generated through L-type calcium channels and amplified by calcium release from intracellular stores, are synchronised with burst firing in subpopulations of GnRH neurones (31). It is, however, unknown whether E2-treatment will induce synchronised calcium oscillations that are associated with E2-induced burst firing of adult GnRH neurones in situ.

Kisspeptin excitatory input to GnRH neurones

Kisspeptin potently depolarises hypothalamic GnRH neurones through a combination of inhibiting an inwardly rectifying potassium (Kir) conductance and activating a nonselective cationic (TRPC) conductance (75–78). To date, kisspeptin is the most potent and efficacious neuropeptide/neurotransmitter to modulate GnRH neuronal activity (26, 27, 58, 79–83). Besides activating TRPC channels in GnRH neurones, kisspeptin also attenuates a resting (barium and cesium sensitive) Kir current. The inhibition of Kir may be critical because Kir channels (e.g. KATP channels) are highly expressed in GnRH neurones and clamp the cells in a negative resting state of −63 mV (56–58). This effect of kisspeptin would also be vital for inhibiting G protein-coupled receptor-activated (μ-opioid, GABAB and MCH) GIRK (Kir) currents which are active in GnRH neurones (57, 58, 60). Moreover, kisspeptin treatment of mature as well as developing GnRH neurones causes increased calcium oscillations and these changes, for the most part, reflect the stimulatory effect of kisspeptin on the plasma membrane via coupling of GPR54 to a phospholipase C signalling pathway (75, 76, 78, 84). Therefore, by inhibiting Kir channels along with the pronounced activation of nonselective cationic (TRPC) channels, kisspeptin depolarises GnRH neurones to threshold (approximately −45 mV) and induces sustained firing, which may be accompanied by a sustained calcium ion influx via calcium channels/TRPC channels and GnRH release during positive-feedback.

Interestingly, GnRH neurones express all of the ‘brain’ TRPC channel subunits (TRPC1, 3, 4, 5, 6, 7), with TRPC1, 4 and 5 being the most prevalent in GnRH neurones (75). It is well known that the current–voltage relationship and mechanism of regulation of TRPC channels are dependent on the channel subunit composition (85). On the basis of the current–voltage relationship, pharmacological profile and mRNA expression, TRPC1, 4, and 5 are key players in mediating the excitatory effects of kisspeptin in GnRH neurones. Traditionally, these channels are known as ‘store operated calcium channels’, although this description may be the result of poorly understood signalling mechanisms (85, 86). Therefore, current research has focused on elucidating the signalling pathway(s) by which kisspeptin activates TRPC channels, and the sources of calcium mobilisation following kisspeptin activation of GnRH neurones. Although most findings appear to indicate that the initial calcium signal comes via plasma membrane channels (75, 78, 84), there is also evidence that kisspeptin activation results in the release of calcium from intracellular stores in GnRH neurones via IP3 receptors (76).

The precise nature by which the kisspeptin signals reach GnRH neurones is not fully understood. Kisspeptin neurones in the AVPV are positively regulated by E2 and are considered to contribute to positive-feedback input to rodent GnRH neurones (87). The AVPV is a complex nucleus that expresses other neurones (transmitters) in addition to kisspeptin, such as dopamine, GABA and glutamate (88, 89). Although anatomical connections from the AVPV to GnRH neurones have been described in a number of studies, the functional interactions have not been elucidated until recently (90). Thus, stimulation of the AVPV and the recording of responses in GnRH neurones revealed that low stimulation rates (< 1 Hz) induced glutamate and GABA synaptic currents in GnRH neurones, whereas higher frequency stimulation (5–10 Hz) induced delayed excitation considered to be a kisspeptin response because it was absent in GPR54 knockout animals and antagonised by a kisspeptin antagonist (90). Therefore, the AVPV kisspeptin neurones may provide a critical excitatory input to GnRH neurones.

Conclusions

Recent experimental findings have greatly increased our understanding of E2 regulation of GnRH neurones. In particular, remarkable progress has been made subsequent to the production of EGFP-GnRH expressing mice and rats, which have allowed direct targeting of the otherwise scattered GnRH neurones. Numerous publications addressing questions concerning E2 regulation of GnRH neuronal activity and its association with calcium signalling and GnRH secretion, coupled with a better understanding of the influence of diurnal rhythms, have advanced the field. However, challenging questions remain concerning the mechanisms by which neuronal burst firing drives pulsatile GnRH release, the integration of presynaptic and postsynaptic E2 actions, as well as the mechanism by which rapid membrane-initiated effects of E2 is coupled to long-term genomic effects. In addition, the mechanism of kisspeptin signalling in GnRH neurones, and the mechanism by which the circadian signals is transmitted to GnRH neurones for the induction of negative- and positive-feedback needs to be elucidated. Future studies need to address these challenging questions to allow a more complete understanding of E2 modulation of GnRH neuronal excitability.

Acknowledgments

The authors thank Drs Martin J. Kelly, Jian Qiu, Yuan Fang and Troy A. Roepke who contributed to the work described in the present review. The work from the authors’ laboratory was supported by PHS grants NS43330, NS38809 and DK68098.

References

  • 1.Micevych P, Sinchak K, Mills RH, Tao L, LaPolt P, Lu JK. The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats. Neuroendocrinology. 2003;78:29–35. doi: 10.1159/000071703. [DOI] [PubMed] [Google Scholar]
  • 2.Micevych P, Bondar G, Kuo J. Estrogen action on neuroendocrine glia. Neuroendocrinology. 2010;91:211–222. doi: 10.1159/000289568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Levine JE, Ramirez VD. Luteinizing hormone-releasing hormone release during the rat estrous cycle and after ovariectomy, as estimated with push-pull cannulae. Endocrinology. 1982;111:1439–1448. doi: 10.1210/endo-111-5-1439. [DOI] [PubMed] [Google Scholar]
  • 4.Chappell PE, Levine JE. Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors. Endocrinology. 2000;141:1477–1485. doi: 10.1210/endo.141.4.7428. [DOI] [PubMed] [Google Scholar]
  • 5.Caraty A, Locatelli A, Martin GB. Biphasic response in the secretion of gonadotrophin-releasing hormone in ovariectomized ewes injected with oestradiol. J Endocrinol. 1989;123:375–382. doi: 10.1677/joe.0.1230375. [DOI] [PubMed] [Google Scholar]
  • 6.Pau K-YF, Berria M, Hess DL, Spies HG. Preovulatory gonadotropin-releasing hormone surge in ovarian-intact rhesus macaques. Endocrinology. 1993;133:1650–1656. doi: 10.1210/endo.133.4.8404606. [DOI] [PubMed] [Google Scholar]
  • 7.Evans NP, Dahl GE, Glover BH, Karsch FJ. Central regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by estradiol during the period leading up to the preovulatory GnRH surge in the ewe. Endocrinology. 1994;134:1806–1811. doi: 10.1210/endo.134.4.8137746. [DOI] [PubMed] [Google Scholar]
  • 8.Karsch FJ, Evans NP. Feedback actions of estradiol on GnRH secretion during the follicular phase of the estrous cycle. Acta Neurobiol Exp (Wars) 1996;56:715–725. doi: 10.55782/ane-1996-1177. [DOI] [PubMed] [Google Scholar]
  • 9.Karsch FJ, Bowen JM, Caraty A, Evans NP, Moenter SM. Gonadotropin-releasing hormone requirements for ovulation. Biol Reprod. 1997;56:303–309. doi: 10.1095/biolreprod56.2.303. [DOI] [PubMed] [Google Scholar]
  • 10.Evans NP, Dahl GE, Mauger DT, Padmanabhan V, Thrun LA, Karsch FJ. Does estradiol induce the preovulatory gonadotropin-releasing hormone (GnRH) surge in the ewe by inducing a progressive change in the mode of operation of the GnRH neurosecretory system. Endocrinology. 1995;136:5511–5519. doi: 10.1210/endo.136.12.7588302. [DOI] [PubMed] [Google Scholar]
  • 11.Evans NP, Dahl GE, Mauger D, Karsch FJ. Estradiol induces both qualitative and quantitative changes in the pattern of gonadotropin-releasing hormone secretion during the presurge period in the ewe. Endocrinology. 1995;136:1603–1609. doi: 10.1210/endo.136.4.7895670. [DOI] [PubMed] [Google Scholar]
  • 12.Christian CA, Mobley JL, Moenter SM. Diurnal and estradiol-dependent changes in gonadotropin-releasing hormone neuron firing activity. Proc Natl Acad Sci USA. 2005;102:15682–15687. doi: 10.1073/pnas.0504270102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Christian CA, Moenter SM. Estradiol induces diurnal shifts in GABA transmission to gonadotropin-releasing hormone neurons to provide a neural signal for ovulation. J Neurosci. 2007;27:1913–1921. doi: 10.1523/JNEUROSCI.4738-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.DeFazio RA, Heger S, Ojeda SR, Moenter SM. Activation of A-type gamma-aminobutyric receptors excites gonadotropin-releasing hormone neurons. Mol Endocrinol. 2002;16:2872–2891. doi: 10.1210/me.2002-0163. [DOI] [PubMed] [Google Scholar]
  • 15.Legan SJ, Coon GA, Karsch FJ. Role of estrogen as initiator of daily LH surges in the ovariectomized rat. Endocrinology. 1975;96:50–56. doi: 10.1210/endo-96-1-50. [DOI] [PubMed] [Google Scholar]
  • 16.Christian CA, Moenter SM. Vasoactive intestinal polypeptide can excite gonadotropin-releasing hormone neurons in a manner dependent on estradiol and gated by time of day. Endocrinology. 2008;149:3130– 3136. doi: 10.1210/en.2007-1098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Chappell PE, Goodall CP, Tonsfeldt KJ, White RS, Bredeweg E, Latham KL. Modulation of gonadotropin-releasing hormone (GnRH) secretion by an endogenous circadian clock. J Neuroendocrinol. 2009;21:339–345. doi: 10.1111/j.1365-2826.2009.01845.x. [DOI] [PubMed] [Google Scholar]
  • 18.Miller JD, Morin LP, Schwartz WJ, Moore RY. New insights into the mammalian circadian clock. Sleep. 1996;19:641–667. doi: 10.1093/sleep/19.8.641. [DOI] [PubMed] [Google Scholar]
  • 19.Van der Beek EM, Horvath TL, Wiegant VM, Van den Hurk RV, Buijs RM. Evidence for a direct neuronal pathway from the suprachiasmatic nucleus to the gonadotropin-releasing hormone system: combined tracing and light and electron microscopic immunocytochemical studies. J Comp Neurol. 1997;384:569–579. doi: 10.1002/(sici)1096-9861(19970811)384:4<569::aid-cne6>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  • 20.Miller BH, Olson SL, Levine JE, Turek FW, Horton TH, Takahashi JS. Vasopressin regulation of the proestrous luteinizing hormone surge in wild-type and clock mutant mice. Biol Reprod. 2006;75:778–784. doi: 10.1095/biolreprod.106.052845. [DOI] [PubMed] [Google Scholar]
  • 21.Vida B, Deli L, Hrabovszky E, Kalamatianos T, Caraty A, Coen CW, Liposits Z, Kalló I. Evidence for suprachiasmatic vasopressin neurons innervating kisspeptin neurons in the rostral periventricular area of the mouse brain: regulation by oestrogen. J Neuroendocrinol. 2010;22:1032–1039. doi: 10.1111/j.1365-2826.2010.02045.x. [DOI] [PubMed] [Google Scholar]
  • 22.Williams WP, III, Jarjisian SG, Mikkelsen JD, Kriegsfeld LJ. Circadian control of kisspeptin and a gated GnRH response mediate the preovulatory luteinizing hormone surge. Endocrinology. 2011;152:595–606. doi: 10.1210/en.2010-0943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Robertson JL, Clifton DK, de la Iglesia HO, Steiner RA, Kauffman AS. Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteninizing hormone surge. Neuroendocrinology. 2009;150:3664–3671. doi: 10.1210/en.2009-0247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Ducret E, Gaidamaka G, Herbison AE. Electrical and morphological characteristics of anteroventral periventricular nucleus kisspeptin and other neurons in the female mouse. Neuroendocrinology. 2010;151:2223– 2232. doi: 10.1210/en.2009-1480. [DOI] [PubMed] [Google Scholar]
  • 25.Suter KJ, Wuarin JP, Smith BN, Dudek FE, Moenter SM. Whole-cell recordings from preoptic/hypothalamic slices reveal burst firing in gonadotropin- releasing hormone neurons identified with green fluorescent protein in transgenic mice. Endocrinology. 2000;141:3731–3736. doi: 10.1210/endo.141.10.7690. [DOI] [PubMed] [Google Scholar]
  • 26.Kuehl-Kovarik MC, Pouliot WA, Halterman GL, Handa RJ, Dudek FE, Partin KM. Episodic bursting activity and response to excitatory amino acids in acutely dissociated gonadotropin-releasing hormone neurons genetically targeted with green fluorescent protein. J Neurosci. 2002;22:213–222. doi: 10.1523/JNEUROSCI.22-06-02313.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Kuehl-Kovarik MC, Pouliot WA, Partin KM, Handa RJ, Dudek FE. Spike-dependent depolarizing afterpotentials contribute to endogenous bursting in gonadotropin releasing hormone neurons. Neuroscience. 2005;134:295–300. doi: 10.1016/j.neuroscience.2005.03.047. [DOI] [PubMed] [Google Scholar]
  • 28.Chu Z, Moenter SM. Physiologic regulation of a tetrodotoxin-sensitive sodium influx that mediates a slow afterdepolarization potential in gonadotropin- releasing hormone neurons: possible implications for the central regulation of fertility. J Neurosci. 2006;26:11961–11973. doi: 10.1523/JNEUROSCI.3171-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kelly MJ, Rønnekleiv OK. Electrophysiological analysis of neuroendocrine neuronal activity in hypothalamic slices. In: Levine JE, editor. Methods in Neurosciences: Pulsatility in Neuroendocrine Systems. San Diego, CA: Academic Press Inc; 1994. pp. 47–67. [Google Scholar]
  • 30.Kelly MJ, Wagner EJ. GnRH neurons and episodic bursting activity. Trends Endocrinol Metab. 2002;13:409–410. doi: 10.1016/s1043-2760(02)00698-7. [DOI] [PubMed] [Google Scholar]
  • 31.Lee K, Duan W, Sneyd J, Herbison AE. Two slow calcium-activated afterhyperpolarization currents control burst firing dynamics in gonadotropin- releasing hormone neurons. J Neurosci. 2010;30:6214–6224. doi: 10.1523/JNEUROSCI.6156-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Duan W, Lee K, Herbison AE, Sneyd J. A mathematical model of adult GnRH neurons in mouse brain and its bifurcation analysis. J Theor Biol. 2011;276:22–34. doi: 10.1016/j.jtbi.2011.01.035. [DOI] [PubMed] [Google Scholar]
  • 33.Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS, McEnery MW, Shin HS. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca2+ channels. Neuron. 2001;31:35–45. doi: 10.1016/s0896-6273(01)00343-9. [DOI] [PubMed] [Google Scholar]
  • 34.Chemin J, Monteil A, Perez-Reyes E, Bourinet E, Nargeot J, Lory P. Specific contribution of human T-type calcium channel isotypes (alpha(1G), alpha(1H) and alpha(1I)) to neuronal excitability. J Physiol. 2002;540:3–14. doi: 10.1113/jphysiol.2001.013269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Erickson KR, Rønnekleiv OK, Kelly MJ. Role of a T-type calcium current in supporting a depolarizing potential, damped oscillations, and phasic firing in vasopressinergic guinea pig supraoptic neurons. Neuroendocrinology. 1993;57:789–800. doi: 10.1159/000126438. [DOI] [PubMed] [Google Scholar]
  • 36.Loose MD, Rønnekleiv OK, Kelly MJ. Membrane properties and response to opioids of identified dopamine neurons in the guinea pig hypothalamus. J Neurosci. 1990;10:3627–3634. doi: 10.1523/JNEUROSCI.10-11-03627.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Huguenard JR, Prince DA. A novel T-type current underlies prolonged Ca2+-dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus. J Neurosci. 1992;12:3804–3817. doi: 10.1523/JNEUROSCI.12-10-03804.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Margaret F, Rees M, Lee J-H. Molecular characterization of a neuronal low-voltage- activated T-type calcium channel. Nature. 1998;391:896–900. doi: 10.1038/36110. [DOI] [PubMed] [Google Scholar]
  • 39.Lee J-H, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klockner U, Schneider T, Perez-Reyes E. Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci. 1999;19:1912–1921. doi: 10.1523/JNEUROSCI.19-06-01912.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Qiu J, Bosch MA, Jamali K, Xue C, Kelly MJ, Rønnekleiv OK. Estrogen upregulates T-type calcium channels in the hypothalamus and pituitary. J Neurosci. 2006;26:11072–11082. doi: 10.1523/JNEUROSCI.3229-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Roepke TA, Xue C, Bosch MA, Scanlan TS, Kelly MJ, Rønnekleiv OK. Genes associated with membrane-initiated signaling of estrogen and energy homeostasis. Endocrinology. 2008;149:6113–6124. doi: 10.1210/en.2008-0769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Lee AW, Kyrozis A, Chevaleyre V, Kow L-M, Zhou J, Devidze N, Zhang Q, Etgen AM, Pfaff DW. Voltage-dependent calcium channels in ventromedial hypothalamic neurones of postnatal rats: modulation by oestradiol and phenylephrine. J Neuroendocrinol. 2008;20:188–198. doi: 10.1111/j.1365-2826.2007.01637.x. [DOI] [PubMed] [Google Scholar]
  • 43.Huguenard JR, McCormick DA. Simulation of the currents involved in rhythmic oscillations in thalamic relay neurons. J Neurophysiol. 1992;68:1373–1383. doi: 10.1152/jn.1992.68.4.1373. [DOI] [PubMed] [Google Scholar]
  • 44.Bosch MA, Hou J, Fang Y, Kelly MJ, Rønnekleiv OK. 17β-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor α and estrogen receptor β. J Comp Neurol. 2009;512:347–358. doi: 10.1002/cne.21901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Qiu J, Bosch MA, Tobias SC, Grandy DK, Scanlan TS, Rønnekleiv OK, Kelly MJ. Rapid signaling of estrogen in hypothalamic neurons involves a novel G protein-coupled estrogen receptor that activates protein kinase C. J Neurosci. 2003;23:9529–9540. doi: 10.1523/JNEUROSCI.23-29-09529.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Qiu J, Bosch MA, Tobias SC, Krust A, Graham S, Murphy S, Korach KS, Chambon P, Scanlan TS, Rønnekleiv OK, Kelly MJ. A G protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis. J Neurosci. 2006;26:5649–5655. doi: 10.1523/JNEUROSCI.0327-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Zhang C, Bosch MA, Rick EA, Kelly MJ, Rønnekleiv OK. 17β-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons. J Neurosci. 2009;29:10552–10562. doi: 10.1523/JNEUROSCI.2962-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Tanaka N, Ishii H, Yin C, Koyama M, Sakuma Y, Kato M. Voltage-gated Ca2+ channel mRNAs and T-type Ca2+ currents in rat gonadotropin-releasing hormone neurons. J Physiol Sci. 2010;60:195–204. doi: 10.1007/s12576-010-0085-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Kato M, Ui-Tei K, Watanabe M, Sakuma Y. Characterization of voltage-gated calcium currents in gonadotropin-releasing hormone neurons tagged with green fluorescent protein in rats. Endocrinology. 2003;144:5118–5125. doi: 10.1210/en.2003-0213. [DOI] [PubMed] [Google Scholar]
  • 50.Cueni L, Canepari M, Lujan R, Emmenegger Y, Watanabe M, Bond CT, Franken P, Adelman JP, Luthi A. T-type Ca2+ channels, SK2 channels and sercas gate sleep-related oscillations in thalamic dendrites. Nat Neurosci. 2008;11:683–692. doi: 10.1038/nn.2124. [DOI] [PubMed] [Google Scholar]
  • 51.Liu S, Shipley MT. Multiple conductances cooperatively regulate spontaneous bursting in mouse olfactory bulb external tufted cells. J Neurosci. 2008;28:1625–1639. doi: 10.1523/JNEUROSCI.3906-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Sun J, Chu Z, Moenter SM. Diurnal in vivo and rapid in vitro effects of estadiol on voltage-gated calcium channels in gonadotropin-releasing hormone neurons. J Neurosci. 2010;30:3912–3923. doi: 10.1523/JNEUROSCI.6256-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Nunemaker CS, DeFazio RA, Moenter SM. Calcium current subtypes in GnRH neurons. Biol Reprod. 2003;69:1914–1922. doi: 10.1095/biolreprod.103.019265. [DOI] [PubMed] [Google Scholar]
  • 54.Spergel DJ. Calcium and small-conductance calcium-activated potassium channels in gonadotropin-releasing hormone neurons before, during, and after puberty. Endocrinology. 2007;148:2383–2390. doi: 10.1210/en.2006-1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Hille B. Potassium channels and chloride channels. In: Hille B, editor. Ion Channels of Excitable Membranes. Sunderland, MA: Sinaur; 2001. pp. 131–165. [Google Scholar]
  • 56.Zhang C, Bosch MA, Levine JE, Rønnekleiv OK, Kelly MJ. Gonadotropin-releasing hormone neurons express KATP channels that are regulated by estrogen and responsive to glucose and metabolic inhibition. J Neurosci. 2007;27:10153–10164. doi: 10.1523/JNEUROSCI.1657-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Zhang C, Bosch MA, Rønnekleiv OK, Kelly MJ. GABAB receptor mediated inhibition of GnRH neurons is suppressed by kisspeptin-GPR54 signaling. Endocrinology. 2009;150:2388–2394. doi: 10.1210/en.2008-1313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Lagrange AH, Rønnekleiv OK, Kelly MJ. Estradiol-17β and μ-opioid peptides rapidly hyperpolarize GnRH neurons: a cellular mechanism of negative feedback? Endocrinology. 1995;136:2341–2344. doi: 10.1210/endo.136.5.7720682. [DOI] [PubMed] [Google Scholar]
  • 59.Xu J, Kirigiti MA, Cowley MA, Grove KL, Smith MS. Suppression of basal spontaneous gonadotropin-releasing hormone neuronal activity during lactation: role of inhibitory effects of neuropeptide Y. Endocrinology. 2009;150:333–340. doi: 10.1210/en.2008-0962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Wu M, Dumalska I, Morozova E, Van den Pol AN, Alreja M. Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction. Proc Natl Acad Sci USA. 2009;106:17217–17222. doi: 10.1073/pnas.0908200106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Chu Z, Takagi H, Moenter SM. Hyperpolarization-activated currents in gonadotropin-releasing hormones (GnRH) neurons contribute to intrinsic excitability and are regulated by gonadal steroid feedback. J Neurosci. 2010;30:13373–13383. doi: 10.1523/JNEUROSCI.1687-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Bond CT, Herson PS, Strassmaier T, Hammond R, Stackman R, Maylie J, Adelman JP. Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J Neurosci. 2004;24:5301–5306. doi: 10.1523/JNEUROSCI.0182-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Bosch MA, Kelly MJ, Rønnekleiv OK. Distribution, neuronal co-localization and 17β-E2 modulation of small conductance calcium-activated K+ channel (SK3) mRNA in the guinea pig brain. Endocrinology. 2002;143:1097–1107. doi: 10.1210/endo.143.3.8708. [DOI] [PubMed] [Google Scholar]
  • 64.Kato M, Tanaka N, Usui S, Sakuma Y. SK channel blocker apamin inhibits slow afterhyperpolarization currents in rat gonadotropin-releasing hormone neurones. J Physiol. 2006;2:431–442. doi: 10.1113/jphysiol.2006.110155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Liu X, Herbison AE. Small-conductance calcium-activated potassium channels control excitability and firing dynamics in gonadotropin-releasing hormone (GnRH) neurons. Endocrinology. 2008;149:3598–3604. doi: 10.1210/en.2007-1631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Kelly MJ, Condon TP, Levine JE, Rønnekleiv OK. Combined electrophysiological, immunocytochemical and peptide release measurements in the hypothalamic slice. Brain Res. 1985;345:264–270. doi: 10.1016/0006-8993(85)91002-9. [DOI] [PubMed] [Google Scholar]
  • 67.Krsmanovic LZ, Stojikovic SS, Merelli F, Dufour SM, Virmani MA, Catt KJ. Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurons. Proc Natl Acad Sci USA. 1992;89:8462–8466. doi: 10.1073/pnas.89.18.8462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Temple JL, Laing E, Sunder A, Wray S. Direct action of estradiol on gonadotropin- releasing hormone-1 neuronal activity via a transcription-dependent mechanism. J Neurosci. 2004;24:6326–6333. doi: 10.1523/JNEUROSCI.1006-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Temple JL, Wray S. BSA-estrogen compounds differentially alter gonadotropin- releasing hormone-1 neuronal activity. Endocrinology. 2005;146:558–563. doi: 10.1210/en.2004-1117. [DOI] [PubMed] [Google Scholar]
  • 70.Abe H, Keen KL, Terasawa E. Rapid action of estrogens on intracellular calcium oscillations in primate LHRH-1neurons. Endocrinology. 2008;149:1155–1162. doi: 10.1210/en.2007-0942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Harrington WR, Kim SH, Funk CC, Madak-Erdogan Z, Schiff R, Katzenellenbogen JA, Katzenellenbogen BS. Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action. Mol Endocrinol. 2006;20:491–502. doi: 10.1210/me.2005-0186. [DOI] [PubMed] [Google Scholar]
  • 72.Noel SD, Keen KL, Baumann DI, Filardo EJ, Terasawa E. Involvement of G-protein couple receptor 30 (GPR30) in rapid action of estrogen in primate LHRH neurons. Mol Endocrinol. 2009;3:349–359. doi: 10.1210/me.2008-0299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Romanò N, Lee K, Ábrahám IM, Jasoni CL, Herbison AE. Non-classical estrogen modulation of presynaptic GABA terminals modulates calcium dynamics in gonadotropin-releasing hormone (GnRH) neurons. Endocrinology. 2008;149:5335–5344. doi: 10.1210/en.2008-0424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Jasoni CL, Todman MG, Strumia MM, Herbison AE. Cell type-specific expression of a genetically encoded calcium indicator reveals intinsic calcium oscillations in adult gonadotropin-releasing hormone neurons. J Neurosci. 2007;27:860–867. doi: 10.1523/JNEUROSCI.3579-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Zhang C, Roepke TA, Kelly MJ, Rønnekleiv OK. Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels. J Neurosci. 2008;28:4423–4434. doi: 10.1523/JNEUROSCI.5352-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Liu X, Lee K, Herbison AE. Kisspeptin excites gonadotropin-releasing hormone (GnRH) neurons through a phosphilipase C/calcium-dependent pathway regulating multiple ion channels. Endocrinology. 2008;149:4605–4614. doi: 10.1210/en.2008-0321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Pielecka-Fortuna J, Chu Z, Moenter SM. Kisspeptin acts directly and indirectly to increase gonadotropin-releasing hormone neuron activity and its effects are modulated by estradiol. Endocrinology. 2008;149:1979–1986. doi: 10.1210/en.2007-1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Constantin S, Caligioni CS, Stojilkovic S, Wray S. Kisspeptin-10 facilitates a plasma membrane-driven calcium oscillator in gonadotropin-releasing hormone-1 neurons. Endocrinology. 2009;150:1400–1412. doi: 10.1210/en.2008-0979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Spergel DJ, Kruth U, Hanley DF, Sprengel R, Seeburg PH. GABA-and glutamate activated channels in green fluorescent protein-tagged gonadotropin- releasing hormone neurons in transgenic mice. J Neurosci. 1999;19:2037–2050. doi: 10.1523/JNEUROSCI.19-06-02037.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.DeFazio RA, Moenter SM. Estradiol feedback alters potassium currents and firing properties of gonadotropin-releasing hormone neurons. Mol Endocrinol. 2002;16:2255–2265. doi: 10.1210/me.2002-0155. [DOI] [PubMed] [Google Scholar]
  • 81.Han SK, Abraham IM, Herbison AE. Effect of GABA on GnRH neurons switches from depolarization to hyperpolarization at puberty in the female mouse. Endocrinology. 2002;143:1459–1466. doi: 10.1210/endo.143.4.8724. [DOI] [PubMed] [Google Scholar]
  • 82.Herbison AE. Physiology of the gonadotropin-releasing hormone neuronal network. In: Neill JD, editor. Knobil and Neill’s Physiology of Reproduction. 3. Boston, MA: Elsevier; 2006. pp. 1415–1482. [Google Scholar]
  • 83.Suter KJ. Control of firing by small (S)-α-amino-3-hydroxy-5methyl-isoxazolepropionic acid-like inputs in hypothalamic gonadotropin releasing-hormone (GnRH) neurons. Neuroscience. 2004;128:443–450. doi: 10.1016/j.neuroscience.2004.06.044. [DOI] [PubMed] [Google Scholar]
  • 84.Kroll H, Bolsover S, Hsu J, Kim S-H, Bouloux P-M. Kisspeptin-evoked calcium signals in isolated primary rat gonadotropin-releasing hormone neurones. Neuroendocrinology. 2011;93:114–120. doi: 10.1159/000321678. [DOI] [PubMed] [Google Scholar]
  • 85.Clapham DE. TRP channels as cellular sensors. Nature. 2003;426:517– 524. doi: 10.1038/nature02196. [DOI] [PubMed] [Google Scholar]
  • 86.Birnbaumer L. The TRPC class of ion channels: a critical review of their roles in slow, sustained increases in intracellular Ca2+ concentrations. Annu Rev Pharmacol Toxicol. 2009;49:395–426. doi: 10.1146/annurev.pharmtox.48.113006.094928. [DOI] [PubMed] [Google Scholar]
  • 87.Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;146:3686–3692. doi: 10.1210/en.2005-0488. [DOI] [PubMed] [Google Scholar]
  • 88.Simerly RB. Hormonal control of the development and regulation of tyrosine hydroxylase expression within a sexually dimorphic population of dopaminergic cells in the hypothalamus. Brain Res Mol Brain Res. 1989;6:297–310. doi: 10.1016/0169-328x(89)90075-2. [DOI] [PubMed] [Google Scholar]
  • 89.Ottem EN, Godwin JG, Krishnan S, Petersen SL. Dual-phenotype GABA/glutamate neurons in adult preoptic area: sexual dimorphism and function. J Neurosci. 2004;24:8097–8105. doi: 10.1523/JNEUROSCI.2267-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Liu X, Porteous R, d’Anglemont de Tassigny X, Colledge WH, Millar R, Petersen SL, Herbison AE. Frequency-dependent recruitment of fast amino acid and slow neuropeptide neurotransmitter release controls gonadotropin-releasing hormone neuron excitability. J Neurosci. 2011;31:2421–2430. doi: 10.1523/JNEUROSCI.5759-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Wang Y, Deshpande M, Payne R. 2-Aminoethoxydiphenyl borate inhibits phototransduction and blocks voltage-gated potassium channels in limulus ventral photoreceptors. Cell Calcium. 2002;32:209– 216. doi: 10.1016/s0143416002001562. [DOI] [PubMed] [Google Scholar]

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