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NEUROENDOCRINOLOGY |
Departments of Internal Medicine and Cell Biology and National Science Foundation Center for Biological Timing, University of Virginia, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Suzanne M. Moenter, Department of Internal Medicine, P.O. Box 800578, Jefferson Park Avenue, University of Virginia, Charlottesville, Virginia 22908. E-mail: . smm4n{at}virginia.edu
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Abstract |
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1 action current/min). Estradiol increased the interval between episodes of increased firing rate determined by Cluster analysis of recordings more than 45 min (OVX+E 38.8 ± 7.2 min, OVX 16.7 ± 2.1 min, n = 6 each). Possible mechanisms of estradiol modulation were examined by simultaneously blocking ionotropic secretion of 
-aminobutyric acid and glutamatergic receptors. This treatment had no effect on cells from OVX mice (n = 10), indicating episodic firing of GnRH neurons is not driven by activation of these receptors. Receptor blockade eliminated estradiol effects on GnRH neurons in the midventral preoptic area (n = 7) but not elsewhere (n = 7). Individual GnRH neurons thus display episodic firing patterns at intervals previously reported for secretory pulses. Estradiol modulates episode frequency to exert feedback control; in a substantial subset of GnRH neurons, estradiol feedback is enforced via GABAergic and/or glutamatergic afferents. |
Introduction |
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Estradiol is an important feedback regulator of GnRH release. LH pulses and volleys of hypothalamic electrical activity, two markers of GnRH secretion, and GnRH release itself are modulated by estradiol (4, 9, 10, 11, 12, 13, 14). Debate continues, however, over the sites and mechanisms of estradiol action on GnRH release. Specifically, does estradiol act directly on GnRH neurons or through estrogen-sensitive afferents? Historically, no evidence for estrogen accumulation (15) or receptor expression (16, 17) was found in GnRH neurons, suggesting estradiol feedback was conveyed to GnRH neurons via estrogen-sensitive afferents (18). Recent studies using more sensitive methods indicate GnRH neurons express ERß, suggesting direct action is also possible (19, 20). Both direct and transsynaptic mechanisms may cooperate in the regulation of GnRH release.
The effects and mechanisms of estradiol feedback on long-term (i.e. minutes to hours) GnRH neuron activity have not been examined directly at the GnRH neuron itself. Recently developed transgenic mice have permitted positive identification of living GnRH neurons through green fluorescent protein (GFP) expression (21, 22). We targeted GFP-identified GnRH neurons for noninvasive single-unit extracellular recordings to monitor firing patterns for up to 3
h. Long-duration recordings were necessary to allow detection of changes in long-term firing patterns that occur on the time scale of GnRH release. Using this approach, we examined the modulatory effects of estradiol on GnRH neuron firing pattern and the role synaptic mechanisms, specifically those activating ionotropic GABAergic and glutamatergic receptors, play in estradiol modulation of firing patterns.
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Materials and Methods |
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Brain slice preparation
All reagents were purchased from Sigma (St. Louis, MO). All solutions were bubbled with 95% O2/5% CO2 mixture throughout the experiments and for at least 30 min before exposure to tissue. Mice were decapitated and the brain was rapidly removed and placed in ice-cold high-sucrose saline solution containing mM 250 sucrose, 3.5 KCl, 26 NaHCO3, 10 glucose, 1.3 NaHPO4, 1.2 MgSO4, 3.8 MgCl2. Coronal 200-µm brain slices were cut with a vibratome (Ted Pella, Inc., Redding, CA) and then incubated for 30 min at room temperature in a solution of 50% high-sucrose saline and 50% normal saline (NS) solution, containing mM 125 NaCl, 3.5 KCl, 26 NaHCO3, 10 glucose, 1.3 NaHPO4, 1.2 MgSO4, 3.8 MgCl2, 2.5 CaCl2. Slices were then transferred to a solution of 100% NS solution at 30–32 C for at least 90 min before recording.
Electrophysiology
Targeted single-unit extracellular recordings were chosen as the approach for this study because this method allows recording from an identified neuron with minimal impact on the behavior of that neuron. Only one cell per slice was recorded; typically one to two slices per animal were used. During recording, slices were placed in a recording chamber continuously superfused at 5–6 ml/min with oxygenated NS solution kept at 30–32 C with an inline-heating unit (Warner Instruments, Hamden, CT). Cells were observed with an Olympus Corp. BX50WI upright fluorescent microscope equipped with infrared differential interference contrast (Opelco, Dulles, VA). GnRH neurons were identified by brief illumination (15–45 sec) at 470 nm to visualize the GFP signal. Cells with bipolar morphology were preferentially targeted in each slice. Recording pipettes (1–3 M
) were made from capillary glass (type 7052, OD/ID 1.65/1.1 mm, World Precision Instruments, Sarasota, FL) using a two-stage pipette puller (Narashige, Japan). Patch pipettes were filled with NS solution or normal HEPES buffered solution containing in mM 150 NaCl, 10 HEPES, 10 glucose, 2.5 CaCl2, 1.3 MgCl2, 3.5 KCl. No difference in firing was observed between these two pipette solutions. Pipettes were targeted to GnRH neurons using an MP-285 micromanipulator (Sutter Instruments, Novato, CA). Slight positive pressure was applied to the pipette before entering the NS solution bath and maintained until reaching a few microns from the target cell. Pressure was released and the pipette was moved next to the GnRH neuron. Initial seal resistances ranged from 4 to 18 M and either remained stable or increased slowly over time up to as high as 31 M. Gentle negative pressure was applied if amplitude of action currents was less than 50 pA; if slice movement was noted during the recording, the pipette was repositioned slightly to compensate. The location of each GnRH neuron studied was mapped on sketches of coronal sections obtained from a mouse brain atlas (23).
The duration of recordings lasted 20–220 min, with mean duration for each treatment group of approximately 60 min. Because of the prolonged interval between secretory pulses, it was anticipated that GnRH neurons might be electrically quiescent for long periods. Shorter-term whole-cell recordings of GFP-identified GnRH neurons also indicated sustained periods of quiescence (21, 24). To resolve whether a long period of quiescence was owing to inactivity of the cell or to having lost the recording, 10–15 mM KCl was added to the bath if no activity was observed for 30 min. If the cell fired in response to this treatment, the data set was truncated for purposes of analysis at the moment before KCl stimulation. If the cell did not respond to KCl, the data set was truncated for analysis at the last minute containing spontaneous action currents.
Drug treatments
To begin to examine the role of synaptic transmission in mediating estradiol effects, long-term targeted extracellular recordings were made from additional GnRH neurons in the presence of ionotropic GABAergic and glutamatergic receptor antagonists (OVX block, n = 10 cells from six mice; OVX+E block, n = 14 cells from five mice). These receptor types were chosen because they are the target of the primary means for synaptic transmission in the hypothalamus (25, 26). Slices were preincubated (15–30 min) and then recorded in NS solution containing 20 µM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 50 µM 2-amino-5-phosphonovaleric acid (APV) to block ionotropic glutamatergic transmission and 20 µM bicuculline to block ionotropic GABAergic transmission. Acute effects of this receptor antagonist mixture were also assessed in cells from OVX mice by switching between control saline and saline containing 20 µM bicuculline, 50 µM APV, and 20 µM CNQX during the recording (switch after 45 min, n = 5).
Data collection
Single-unit extracellular recordings were made using an EPC-7 or EPC-8 amplifier (HEKA, Germany) with Igor Pro software (Instrutech, Port Washingtion, NY) running on a G4 Macintosh computer (Apple Computer, Cupertino, CA) to acquire data. Recordings were made in voltage-clamp mode with a holding potential of 0 mV, filtering at 10 kHz, and digitized with an ITC-18 acquisition interface (Instrutech). Action currents (events), the membrane currents associated with action potential firing, were detected using Pulse Control Event Tracker software (Instrutech). Events were identified using the following Event Tracker settings: 10 µsec sampling interval, -50 to -150 pA threshold (depending on noise levels and initial action current amplitude), 1 point over threshold to trigger. Noise typically ranged from 20 to 25 pA peak to peak. For each event, the time of the event and 10 msec centered on the event were digitized and stored to a data file. To eliminate artifacts, we designed a program to detect spurious events using a minimum event width of 0.05 msec at half-peak amplitude. Using custom programs written for Igor Pro (Instrutech), events (action currents) were counted and binned at 1-min intervals to identify changes in long-term firing patterns. Using Excel (Microsoft Corp., Redmond, WA), binned data were evaluated for several criteria as detailed below.
Data analysis
Our goal was to examine long-term firing patterns under various conditions, looking for episodes of increased firing rate (referred to as episodes hereafter). This requires recordings of sufficient duration for multiple episodes to occur; the duration of observation would naturally increase as episodes become further apart. We were successful in obtaining 27 recordings long enough to detect episodes of increased firing rate using the Cluster 7 algorithm (27, 28). Two of these were arrhythmic as described below so that the total number of cells analyzed by Cluster was 25 (n = 6 cells each OVX, OVX+E, OVX+E block, n = 7 OVX block). Cluster 7 compares clusters of points by pooled t testing to look for nadirs and peaks over time. Using peak and nadir clusters of 4 and 6 points, respectively, Cluster 7 identified episodes and calculated the interepisode intervals for recordings with multiple identified episodes. Because it requires a string of data flanking a peak for positive identification, Cluster 7 often missed episodes very near the beginning or end of data streams; obvious episodes in these positions that could not be identified by Cluster 7 analysis were identified by eye (e.g. see first and last episode in Fig. 4A
, lower panel). Some recordings did not display two or more episodes for one of two reasons. First, some recordings were of insufficient duration for more than one episode to occur given the average interepisode intervals (n = 25 total, n = 8 OVX, n = 8 OVX+E, n = 3 OVX block, n = 6 OVX+E block). Second, two recordings that were of sufficient duration did not exhibit identifiable changes in firing rate; one was continuously active and one showed very sparse activity. These 27 recordings were analyzed using alternative methods discussed below.
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Comparison of percent quiescence was performed using a Wilcoxon rank-sum test. Mean frequency, interepisode interval, and quiescence duration were compared by one-way ANOVA followed by post hoc analysis with both Fisher’s protected least significant difference and Student-Newman-Keuls for pair-wise comparisons when appropriate.
LH immunoassay
Trunk blood was collected from each mouse at the time of brain slice preparation. Serum LH concentration was determined by a modified supersensitive two-site sandwich immunoassay described previously (29, 30). Mouse LH reference preparation (AFP-5306A) provided by the National Hormone and Pituitary Program was used as standard. The assay sensitivity was 0.07 ng/ml; intra- and interassay coefficients of variation were 7.7% and 14%, respectively.
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The firing pattern of GnRH neurons differs from that of non-GnRH neurons
Using a targeted single-unit recording technique, GnRH neuron firing patterns were recorded for up to 3.5 h. GnRH neurons had a mean firing rate (total events/duration of recording) of 0.20–0.45 Hz that did not differ among the four treatment groups (P > 0.25). There was a high degree of variability in firing rate in GnRH neurons because firing occurred in episodes separated by quiescent periods (Fig. 1A). Tetrodotoxin (500 nM) eliminated all activity in GnRH neurons (n = 5), indicating the detected events were because of sodium-dependent action potentials (data not shown). The episodic firing pattern observed in GnRH neurons was markedly different from that of magnocellular neurons in the paraventricular nucleus of the hypothalamus (Fig. 1B), in which firing rate was relatively constant (2–3 Hz, n = 5 cells), consistent with previous reports (31). Of interest, the action current waveforms of GnRH neurons (Fig. 1C) and non-GnRH neurons (Fig. 1D) also differed qualitatively.
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, top), whereas for the OVX+E group, firing patterns typically consisted of longer periods of quiescence (Fig. 2B, top). Short-term firing patterns in both OVX and OVX+E states typically consisted of brief firing bursts separated by a few seconds (Fig. 2, middle). Action current waveforms (Fig. 2, bottom) were qualitatively similar in both OVX and OVX+E states. The remainder of this report deals with estradiol actions on the long-term firing patterns because these occur on an interval consistent with secretory pulses from these cells; short-term patterns will be considered in a separate report.
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1 event/min) and duration of quiescence (defined as number of consecutive 1-min bins containing 1 event/min). Quantitatively, a significantly greater percentage of quiescence was observed in cells from OVX+E mice (49% ± 6%, n = 14) than those from OVX mice (18% ± 5%, n = 14, P < 0.002). Further, the duration of quiescence was greater (P < 0.01) for cells from OVX+E mice (6.9 ± 1.4 min) than those from OVX mice (1.7 ± 0.4 min), suggesting that estradiol may reorganize GnRH neuron firing patterns.
Recordings longer than 45 min were further analyzed with the Cluster 7 algorithm to determine if significant episodes of increased firing rate occurred in either group. Figure 3 shows representative examples of firing patterns from both groups with episodes detected by Cluster 7 marked with an asterisk. Interepisode interval was greater for cells from OVX+E mice (38.8 ± 7.2 min), compared with cells from OVX mice (16.7 ± 2.1 min, P < 0.02). Together these findings suggest estradiol-induced alterations in GnRH secretion are reflected directly at the GnRH neuron as changes in firing pattern.
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-aminobutyric acid A (GABAA) receptor antagonist bicuculline, the N-methyl-D-aspartate receptor antagonist APV and the 
-amino-3-hydroxy-S-methylisoxazale-4-proprionic acid receptor antagonist CNQX. In GnRH neurons from OVX control mice, there was no effect of the receptor antagonist cocktail on any measure of firing activity (i.e. interepisode interval, quiescence, or mean firing rate, Fig. 4
, see Figs. 6 and 7 for summary, n = 10). This indicates activity was not generated or significantly modulated by ionotropic GABAergic or glutamatergic communication in our slice preparation. This finding held true for all measures described above and whether recordings were made following preincubation in the receptor antagonist cocktail (Fig. 4A) or after acute receptor blockade (Fig. 4B).
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). Cells that responded are referred to as "responders," those that did not as "nonresponders." All but one of the cells that was recorded for sufficient duration for Cluster analysis (n = 5 of 6) fell into the responder group. As a consequence, the estradiol-mediated increase of interepisode interval as determined by Cluster analysis was reversed by the receptor antagonist cocktail (Fig. 6A).
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) or duration of quiescence (Fig. 6C). Although no differences were observed in these measures for the complete data set, cells from OVX+E mice recorded in the receptor antagonist mixture fell into two groups, as mentioned above, with regard to the quiescence measures examined. We thus examined the distribution of data and compared values above the median to those below the median for mean percent quiescence and quiescence duration. The distribution of percent quiescence reveals the two groups, responders and nonresponders, within the OVX+E block group (Fig. 7A, closed triangles). Specifically, values above the median of the OVX+E block group were similar to those from the untreated OVX+E group (Fig. 7A, open triangles), whereas values below the median of the OVX+E block group were similar to those from the OVX and OVX block groups (Fig. 7, circles, summary in Fig. 7B). A similar pattern is seen when duration of quiescence was examined in this manner (Fig. 7, C and D). Percentage quiescence rank order matched that of duration of quiescence, showing the same cells demonstrated both of these trends.
The differences revealed by the arbitrary division into two groups around the median are of interest with regard to the anatomical location of cells in each group. Cells from OVX+E animals that were responsive to the receptor antagonists were predominantly located in the midventral preoptic area (5 of 7, Fig. 8). The only designated unresponsive cell located within this area was on the cusp between values from both OVX and OVX+E animals. Other unresponsive cells were widely distributed but typically located outside the midventral preoptic area (6 of 7, Fig. 8). These data suggest that communication of estradiol actions to GnRH neurons may occur through phenotypically different mediators, depending on the location of specific subpopulations of GnRH neurons.
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Discussion |
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The present findings are consistent with several reports of the effect of estradiol on indirect measures of GnRH-pulse generator activity in rodents. For example, estradiol reduces frequency of volleys of hypothalamic electrical activity associated with LH release (32). Consistent with this, sharp electrode recordings of GnRH neurons in guinea pigs demonstrated acute inhibition of firing by bath application of estradiol (33); further work in this model implied activation of an inward-rectifying potassium channel in this inhibition (34). Previous studies using whole-cell current clamp to examine GnRH neurons directly have demonstrated that GnRH-GFP neurons in acute slice preparations are capable of firing spontaneous action potentials (21) or single episodes of increased firing flanked by periods of quiescence (24). The present data extend these findings by revealing, for the first time, not only repeated bouts of activity from individual GnRH neurons that occur with an interval relevant to GnRH release but also in vivo estradiol modulation of these episodic firing patterns in a manner consistent with estradiol-induced changes in LH release. This study also has implications from a technical standpoint. Specifically, reproductive changes elicited through use of an in vivo animal model (OVX vs. OVX+E) produced changes in the GnRH neurosecretory system that could be documented and studied in acutely prepared brain slices in the absence of estradiol.
Possible mechanisms of estradiol modulation were examined to determine if estradiol-sensitive afferents were involved in mediating these effects. The choice to investigate ionotropic GABAergic and glutamatergic neurotransmitter systems in this regard was based on several factors. First, these are the dominant excitatory and inhibitory neurotransmitters in the hypothalamus (25, 26), so these transmitter systems are likely candidates to be used by interneurons within local circuits interacting with GnRH neurons or perhaps between GnRH neurons themselves. With regard to the latter, GnRH neurons possess small clear vesicles indicative of classical neurotransmitters (35) and GT1 cells (36) and prenatal GnRH neurons (37) have been shown to synthesize GABA. Second, GABA and glutamate receptors have been identified in GnRH neurons (18, 21, 38). Third, estrogen-sensitive neurons located near or projecting to the region of GnRH neurons in the preoptic area and hypothalamus synthesize and secrete GABA (39) or glutamate (40, 41). Moreover, estradiol has been shown to increase the density of synaptic contacts in the hippocampus (42) as well as to enhance the postsynaptic response following activation of ionotropic receptors (43). Fourth, indirect evidence from whole-animal studies suggests both GABA and glutamate affect LH release (18, 44). Finally, because we wished to determine whether estradiol feedback was transmitted indirectly to GnRH neurons, we chose to block simultaneously GABAergic and glutamatergic receptors. Simultaneous blockade should eliminate dominant forms of neural communication, consistent with this goal, as well as minimize difficulties in interpretation that arise because of interactions between these systems in the complex networks present in the brain slice.
For these reasons, we hypothesized estradiol-induced effects on GnRH neuron firing patterns were conveyed through a pathway involving GABAergic and/or glutamatergic neurons. Approximately half of the neurons from estradiol-treated mice responded to blockade of ionotropic GABAergic and glutamatergic receptors by reverting to OVX-like long-term firing patterns. This suggests that estradiol effects are mediated by activation of these receptors in a sizable subpopulation of GnRH neurons and supports previous descriptions of functional heterogeneity among GnRH neurons (45, 46). Interestingly, GnRH neurons from OVX+E mice that responded to blockade were located within or just outside the midventral preoptic area. In contrast, nonresponsive GnRH neurons were typically located outside this area, indicating a possible correlation between anatomical location and use of GABA and/or glutamate acting through ionotropic receptors as mediators of estradiol effects.
In addition to anatomical location, there are other possible explanations for a lack of response to ionotropic receptor blockade in half of the GnRH neurons examined from OVX+E mice. First, slice preparation could damage local network circuitry, possibly affecting some GnRH neurons more than others, depending on location or innervation. In this regard, functional synapses have been demonstrated in the absence of the presynaptic cell body (47), but it is important to point out that indirect action through multiple interneurons could be compromised in slice preparations. Second, recent evidence supports the possibility of direct effects of estradiol acting through the ß isoform of the estrogen receptor on GnRH neurons (19, 20). Direct action of estradiol on GnRH neurons could explain why some cells did not respond to blockade of ionotropic GABAergic and glutamatergic receptors because interneurons would not be required for direct effects. Third, estradiol effects could be mediated by afferents that communicate through other neurotransmitters such as norepinephrine (18), NPY (48, 49), or opioid peptides (50).
Another intriguing observation arising from these studies was that blockade of ionotropic GABAergic and glutamatergic transmission had no significant impact on the long-term firing patterns of GnRH neurons from OVX mice. Eliminating both steroid feedback by ovariectomy and specific transmitted effects by receptor blockade permits speculation about the origin of GnRH neuron rhythmicity. Continued episodic firing from these cells following receptor blockade is consistent with the hypothesis that individual GnRH neurons contain the oscillatory mechanisms necessary for inherent pulse generation. The notion that GnRH neurons are intrinsically rhythmic is supported by work on immortalized GnRH neurons, GT1 cells (51). Cultures of GT1 cells exhibit pulsatile secretory patterns (52, 53, 54). Studies of patterns in membrane recycling associated with exocytosis (55) and action potential firing (28) have extended this observation to the level of individual or small clusters of GT1 cells. Recent work on primary cultures of GnRH neurons examining action potential firing (56) or oscillations in intracellular calcium (57) concur with these findings in GT1 cells.
The hypothesis that long-term changes in firing pattern associated with GnRH release emerge from an oscillator intrinsic to GnRH neurons fits well with our current observations that estradiol feedback alters neuronal networks that influence GnRH firing patterns. We propose the role of estradiol feedback through these networks is to adjust the pattern of GnRH neuron activity, rather than the overall firing rate. In this way, estradiol can regulate the interval of GnRH release as needed to drive shifts in fertility, without affecting the fundamental oscillatory mechanism. The data have implications at the mechanistic level for shifts among different reproductive states that are driven by changes in estradiol feedback such as parts of the reproductive cycle (4, 58), seasonal transitions (59), and the attainment of puberty (60).
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Acknowledgments |
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Footnotes |
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Abbreviations: APV, 2-Amino-5-phosphonovaleric acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; GABA, -aminobutyric acid; GFP, green fluorescent protein; NS, normal saline; OVX, ovariectomized; OVX + E, ovariectomized mice treated with estradiol.
Received January 30, 2002.
Accepted for publication February 25, 2002.
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and ß messenger ribonucleic acids in adult gonadotropin-releasing hormone neurons. Endocrinology 140:5195–5201-aminobutyric acid-evidence for an autocrine regulation. Eur J Neurosci 10:1145–1152[CrossRef][Medline]
-aminobutyric acid and gonadotropin-releasing hormone during neuronal migration through the olfactory system. Endocrinology 137:5415–5420[Abstract]
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A. K. Greenwood and R. D. Fernald Social Regulation of the Electrical Properties of Gonadotropin-Releasing Hormone Neurons in a Cichlid Fish (Astatotilapia burtoni) Biol Reprod, September 1, 2004; 71(3): 909 - 918. [Abstract] [Full Text] [PDF]
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V. Matagne, G. Rasier, M.-C. Lebrethon, A. Gerard, and J.-P. Bourguignon Estradiol Stimulation of Pulsatile Gonadotropin-Releasing Hormone Secretion in Vitro: Correlation with Perinatal Exposure to Sex Steroids and Induction of Sexual Precocity in Vivo Endocrinology, June 1, 2004; 145(6): 2775 - 2783. [Abstract] [Full Text] [PDF]
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S. D. Sullivan and S. M. Moenter Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: Implications for a common fertility disorder PNAS, May 4, 2004; 101(18): 7129 - 7134. [Abstract] [Full Text] [PDF]
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S. D. Sullivan and S. M. Moenter {gamma}-Aminobutyric Acid Neurons Integrate and Rapidly Transmit Permissive and Inhibitory Metabolic Cues to Gonadotropin-Releasing Hormone Neurons Endocrinology, March 1, 2004; 145(3): 1194 - 1202. [Abstract] [Full Text] [PDF]
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C. Xu, X.-Z. Xu, C. S. Nunemaker, and S. M. Moenter Dose-Dependent Switch in Response of Gonadotropin-Releasing Hormone (GnRH) Neurons to GnRH Mediated through the Type I GnRH Receptor Endocrinology, February 1, 2004; 145(2): 728 - 735. [Abstract] [Full Text] [PDF]
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C. S. Nunemaker, R. A. DeFazio, and S. M. Moenter Calcium Current Subtypes in GnRH Neurons Biol Reprod, December 1, 2003; 69(6): 1914 - 1922. [Abstract] [Full Text] [PDF]
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M. Kato, K. Ui-Tei, M. Watanabe, and Y. Sakuma Characterization of Voltage-Gated Calcium Currents in Gonadotropin-Releasing Hormone Neurons Tagged with Green Fluorescent Protein in Rats Endocrinology, November 1, 2003; 144(11): 5118 - 5125. [Abstract] [Full Text] [PDF]
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S. D. Sullivan and S. M. Moenter Neurosteroids Alter {gamma}-Aminobutyric Acid Postsynaptic Currents in Gonadotropin-Releasing Hormone Neurons: A Possible Mechanism for Direct Steroidal Control Endocrinology, October 1, 2003; 144(10): 4366 - 4375. [Abstract] [Full Text] [PDF]
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S. D. Sullivan, R. A. DeFazio, and S. M. Moenter Metabolic Regulation of Fertility through Presynaptic and Postsynaptic Signaling to Gonadotropin-Releasing Hormone Neurons J. Neurosci., September 17, 2003; 23(24): 8578 - 8585. [Abstract] [Full Text] [PDF]
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H. T. Jansen, C. Cutter, S. Hardy, M. N. Lehman, and R. L. Goodman Seasonal Plasticity within the Gonadotropin-Releasing Hormone (GnRH) System of the Ewe: Changes in Identified GnRH Inputs and Glial Association Endocrinology, August 1, 2003; 144(8): 3663 - 3676. [Abstract] [Full Text] [PDF]
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S. M. Leupen, S. A. Tobet, W. F. Crowley Jr., and K. Kaila Heterogeneous Expression of the Potassium-Chloride Cotransporter KCC2 in Gonadotropin-Releasing Hormone Neurons of the Adult Mouse Endocrinology, July 1, 2003; 144(7): 3031 - 3036. [Abstract] [Full Text] [PDF]
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C. S. Nunemaker, M. Straume, R. A. DeFazio, and S. M. Moenter Gonadotropin-Releasing Hormone Neurons Generate Interacting Rhythms in Multiple Time Domains Endocrinology, March 1, 2003; 144(3): 823 - 831. [Abstract] [Full Text] [PDF]
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 R. A. DeFazio, S. Heger, S. R. Ojeda, and S. M. Moenter Activation of A-Type {gamma}-Aminobutyric Acid Receptors Excites Gonadotropin-Releasing Hormone Neurons Mol. Endocrinol., December 1, 2002; 16(12): 2872 - 2891. [Abstract] [Full Text] [PDF]
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R. A. DeFazio and S. M. Moenter Estradiol Feedback Alters Potassium Currents and Firing Properties of Gonadotropin-Releasing Hormone Neurons Mol. Endocrinol., October 1, 2002; 16(10): 2255 - 2265. [Abstract] [Full Text] [PDF]
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