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-Aminobutyric Acid Can Excite Gonadotropin-Releasing Hormone Neurons
Department of Internal Medicine and Cell Biology, University of Virginia (S.M.M.), Charlottesville, Virginia 22908; and Department of Physiology and Biophysics, Miller School of Medicine, University of Miami (R.A.D.), Miami, Florida 33136
Address all correspondence and requests for reprints to: Dr. Suzanne M. Moenter, Department of Internal Medicine, P.O. Box 800578, University of Virginia, Charlottesville, Virginia 22908. E-mail: smm4n{at}virginia.edu.
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Abstract |
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-Aminobutyric acid (GABA) provides a major synaptic input to GnRH neurons. GnRH neurons maintain high intracellular chloride levels and respond to exogenous GABA with depolarization and action potential firing. We examined the role of synaptic GABA type A receptor (GABAAR) activation on the firing activity of GnRH neurons. Targeted extracellular recordings were used to detect firing activity of GnRH neurons in brain slices from adult female mice. Because the brain slice preparation preserves both glutamatergic and GABAergic neuronal networks, the effects of GABAARs on GnRH neurons were isolated by blocking ionotropic glutamatergic receptors (iGluR). With iGluR blocked, many GnRH neurons remained spontaneously active. Consistent with an excitatory role for GABA, subsequent blockade of GABAARs suppressed the firing rate in active cells from diestrous females by approximately 40% (P < 0.05; n = 10). GABAAR blockade did not affect inactive cells (n = 7), indicating that GABAAR-mediated inhibition was not responsible for the lack of firing. In prenatally androgenized females, GnRH neurons exhibit larger, more frequent GABAergic postsynaptic currents than control females. Most cells from prenatally androgenized animals fired spontaneously, and the firing rate was suppressed approximately 80% after GABAAR blockade (P < 0.01; n = 8). Blocking GABAAR without blocking iGluRs increased the firing rate in GnRH neurons from diestrous females (P < 0.05; n = 6), perhaps attributable to hyperexcitability within the slice network. Our results indicate that GABAergic inputs help generate a portion of action potentials in GnRH neurons; this fraction depends on the level of GABA transmission and postsynaptic responsiveness. The complexities of the GnRH neuron response to GABA make this a potentially critical integration point for central regulation of fertility. |
Introduction |
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-aminobutyric acid (GABA) has long been implicated in the central regulation of reproduction. GABAergic synapses have been identified on GnRH neurons (1, 2, 3), and GnRH neurons express GABAA receptors (GABAARs) (4, 5, 6). Electrophysiological studies have shown that GABAARs on GnRH neurons are functional (7) and synaptically activated (8, 9, 10, 11). Correlative measures of preoptic area GABA levels and LH release suggest an inverse relationship during both pulsatile and surge modes of LH release (12, 13, 14). Blockade of GABAARs in vivo is correlated with advancement of puberty (15), whereas central application of GABA has the opposite effect. In rodents, some data suggest that inhibition of reproductive neuroendocrine function by GABAA agonists may develop around the postnatal wk 3–4 (16). In contrast to the inhibitory actions induced by widespread activation of GABAARs, targeted increases in GABA near the terminals of GnRH neurons in vivo resulted in stimulation, reflected in increased LH levels (17). In vitro studies have also indicated either suppression or enhancement of GnRH release from brain explants or GnRH neural activity, depending on the region studied and the age of the animal (18, 19, 20). An impediment to interpreting the above-mentioned studies is that the sites of action of the various treatments cannot be determined and indeed are probably multiple. Furthermore, global application of GABA agonists over tens of minutes is difficult to interpret in the same context as synaptic GABAAR activation, which occurs on the scale of milliseconds. Direct studies of the consequence of GABAAR activation on GnRH neurons are limited. Gramicidin-perforated patch voltage-clamp studies revealed that GnRH neurons maintain high levels of chloride relative to most mature neurons (21). Chloride is the main charge carrier through the GABAAR (22), and intracellular levels of this ion determine the response to GABAAR activation. Most adult neurons maintain low intracellular chloride levels, resulting in hyperpolarization (inhibition), whereas high levels of intracellular chloride can lead to depolarization and excitation. In an increasing subset of adult neurons from widespread brain regions, depolarization and even excitation to fire action potentials have been observed in response to GABA (23, 24, 25, 26, 27, 28, 29). Local application of GABA near GnRH neurons induces action potential firing (21); in contrast, bath application of GABA has been reported to hyperpolarize adult GnRH neurons, but depolarize prepubertal GnRH neurons in current-clamp studies (20).
Both of the above-mentioned studies examined the effects of exogenous GABA with direct recordings of GnRH neurons. Because both bath and local administration produce stimulation of GABAARs that is supraphysiological, the response to synaptic GABA release is important to evaluate. One study explored the effects of GABAAR antagonists on membrane potential and action potential firing in gramicidin-perforated patch, current-clamp experiments and found that a majority of GnRH neurons were depolarized and/or excited by blocking GABAAR (30), consistent with an inhibitory role for endogenous GABA. One possible caveat is that in most slice preparations, there are intact glutamatergic and GABAergic neuronal networks. Bath application of GABAAR antagonists will block not only GABAARs on GnRH neurons, but also those on all neurons in the brain slice, resulting in increased glutamatergic synaptic activity, hyperexcitability, and seizure-like discharges (31, 32, 33). In this study we examine the effects of blocking GABAAR in the presence and absence of ionotropic glutamate receptor (iGluR) antagonists and in mouse models with different levels of endogenous GABA synaptic transmission. Together, our data indicate that endogenous activation of GABAAR helps drive action potential firing in GnRH neurons.
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Materials and Methods |
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Brain slice preparations
Brain slices were prepared with slight modifications (35) of previous reports (36, 37). All solutions were bubbled with a 95% O2/5% CO2 mixture throughout the experiments and at least 15 min before exposure to the tissue. Mice were decapitated, and brains were rapidly removed and placed in ice-cold high-sucrose/low-sodium saline solution containing 250 mM sucrose, 3.5 mM KCl, 26 mM NaHCO3, 10 mM glucose, 1.25 mM NaHPO4, 1.2 mM MgSO4, and 2.5 mM MgCl2. Coronal 200-µm brain slices through the preoptic area and anterior hypothalamus were cut with a Vibratome 3000 (Technical Products International, Inc., St. Louis, MO). Slices were incubated for 30 min at 30–32 C in a solution of 50% high-sucrose saline and 50% normal saline (NS) containing 10 mM glucose, 1.3 mM NaHPO4, 1.2 mM MgSO4, and 2.5 mM CaCl2, then transferred to a solution of 100% NS at room temperature and kept at least 60 min before recording.
Electrophysiology and recordings
Targeted extracellular recordings (also known as loose-patch) were used for this study (37). This method does not break the cell membrane and thus does not disturb the normal intracellular milieu, including chloride concentrations. This allows the normal changes in the firing activity of a neuron in response to changes in GABA transmission to be evaluated.
Brain slices were placed in a recording chamber continuously superfused with oxygenated NS solution, kept at 29–31 C, and mounted on an Olympus BX50WI upright fluorescent microscope with infrared differential interference contrast (Opelco, Dulles, VA). Recording pipettes (1–3.5 M
) were filled with a HEPES-buffered external solution containing 150 mM NaCl, 10 mM HEPES, 10 mM glucose, 2.5 mM CaCl2, 1.3 mM MgCl2, and 3.5 mM KCl and were placed in contact with the GnRH neurons using MP-285 micromanipulator (Sutter Instruments, Novato, CA). Seal resistances ranged from 5–32 M, consistent with the loose-patch configuration. The location of each cell was mapped to illustrations from an atlas (38); in this series of experiments, no difference in response was attributable to location.
Drug treatments
After allowing for recording stabilization (
5 min), each recording consisted of control, treatment, and recovery periods of at least 5 min each. In experiments 1 and 2, iGluRs were blocked by inclusion in the bath solution of 20 µM D(–)2-amino-5-phosphonovaleric acid (APV) and 20 µM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) to block N-methyl-D-aspartate and 
-amino-3-hydroxy-5-methylisoxazale-4-proprionic acid (AMPA) receptors, respectively. In our previous studies of GABAergic PSCs, these blockers effectively eliminated currents mediated by iGluRs, as demonstrated by an absence of PSCs upon subsequent blockade of GABAARs (35, 39). Blockers of iGluRs were omitted in experiment 3. GABAARs were blocked with either bicuculline methiodide (bic; 20 µM) or picrotoxinin [picrotoxin (picro); 100–150 µM[. Most cells were treated with picro despite the increased difficulty of reversal because of the selectivity and high affinity of this drug for GABAAR. Bic, although easier to wash out, has been reported to broaden action potential waveforms due to blockade of certain types of potassium channels (40). Because this effect on potassium channels could be depolarizing, any such cross-reactivity would confound interpretation of the data. To verify recording integrity and cell health, cells were depolarized with bath application of an elevated potassium solution (10–15 mM KCl) if no spontaneous firing or recovery of spontaneous firing after treatment was observed. If a cell fired in response to this treatment, data were included; if not, the cell was discarded, because inhibition of firing activity could have been due to either loss of recording or death of the cell.
Data collection
Data were recorded using an EPC-8 amplifier (HEKA, Mahone Bay, Nova Scotia, Canada) with Igor Pro (Wavemetrics, Lake Oswego, OR) running on a G4 Macintosh computer (Apple Computer, Cupertino, CA). Recordings were made in voltage-clamp mode with a pipette holding potential of 0 mV. The low resistance seals (<50 M) minimize the influence of the pipette potential on the cell’s membrane potential and changing the pipette potential does not alter GnRH neuron activity, allowing us to periodically verify the low resistance of the seal with minimal impact on firing activity. Signals were filtered at 10 kHz, digitized with an ITC-18 acquisition interface (Instrutech, Port Washington, NY). Pulse Control Event Tracker (Instrutech) software was used to detect the membrane currents associated with action potential firing. Action currents (events) were identified using previously described settings (36, 37).
Data analysis
Using custom programs written for Igor Pro, events were counted and binned at 10-sec intervals to identify changes in the mean firing rate (number of events per recording time). The first 2 min after solution switch were omitted from quantitative analysis to allow time for solution exchange and drug penetration of the slice. Firing rates during various phases of the recording were compared using a two-tailed Wilcoxon matched-pairs, signed-rank test; P < 0.05 was considered significant. The criterion for an effect on firing rate was a change greater than 25%.
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Results |
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). Treatment with picro (n = 5) or bic (n = 2) failed to increase the firing rate, suggesting that GABAAR-mediated inhibition was not responsible for the lack of activity. These cells fired when depolarized by KCl, indicating good recording integrity and cell health. Ten cells were spontaneously active (Fig. 1B). In these cells, subsequent blockade of GABAARs resulted in a mild (41 ± 14%), but significant (P < 0.05), suppression of GnRH neuron firing. The firing rate was suppressed in eight cells, remained unchanged in one cell, and increased in one cell (Fig. 4A). These data are consistent with the excitatory action of endogenous GABA in diestrous females.
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) and picro (Fig. 2B) markedly (78 ± 10%) reduced the firing rate. Individually seven cells decreased firing, and one was unchanged (24% decrease; Fig. 4B
). These data suggest that in an animal model with increased GABAergic transmission, synaptic activation of GABAAR can be excitatory.
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Six GnRH neurons from six diestrous control females were studied. Consistent with GABAAR antagonist-induced hyperexcitability in the hypothalamic brain slice, when GABAARs were blocked without previous blockade of iGluRs, all six neurons exhibited a marked 5- to more than 100-fold increase in the firing rate (P < 0.05; Figs. 3, A and C, and 4C).
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Discussion |
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In examining the effects of GABAAR activation, it is important to maintain a cell’s native chloride milieu, because this ion is the main charge carrier through the channel (22). The three most common approaches are gramicidin-perforated patch, on-cell recordings, or targeted extracellular recordings; each has strengths and weaknesses (37, 45, 46). Perforated patch recordings are formed using on-cell patch-clamp methods and inclusion of a pore-forming antibiotic, such as gramicidin, in the pipette solution. This method, like on-cell or whole-cell recording, requires frequent monitoring of basic recording parameters (seal resistance and access resistance) for potential rupture of the membrane and subsequent dialysis of the cell with pipette solution. Monitoring these basic properties involves changing the membrane potential. We chose targeted extracellular recordings because these are minimally disruptive to the cell. Furthermore, the loose seal allows periodic monitoring of seal resistance without influencing the cell’s membrane potential. The activity recorded with the targeted extracellular approach is that of the cell based on its intrinsic conductances and synaptic inputs, with minimal interference from the experimenter. A disadvantage to this approach is that a lack of firing activity cannot be interpreted as a quiet cell vs. a technical problem; we thus included a positive control for recordings from quiescent cells by mildly depolarizing them with potassium at the end of a recording.
Our results differ from those of a previous study of the effects of endogenous GABA activation (30). In that report, blockade of GABAAR with bic was depolarizing and/or excitatory, even in the presence of tetrodotoxin. Although tetrodotoxin blocks sodium-dependent action potentials, it does not eliminate synaptic function. Some neurons, including GnRH neurons, receive considerable synaptic input in the absence of action potential firing (9, 10, 11, 47, 48, 49). In the network of the brain slice preparation, treatments affect not only the neuron of interest, but all cells containing receptors for that treatment. Responses may thus be due to direct action of the antagonist on the cell of interest and/or indirect actions on other cells within the neuronal network of the slice that subsequently influence the cell of interest.
In this regard, we believe a difference in experimental approach may help account for the discrepancy. In the first two experiments of the present study, iGluRs, which mediate the majority of excitatory transmission within the brain slice neuronal network, were blocked before inhibition of GABAARs. Blocking iGluRs prevents hyperexcitability upon subsequent blockade of GABAARs throughout the slice. Because activation of GABAARs is inhibitory in most adult neurons, blocking these receptors leads to a loss of most inhibition within the network. This causes disinhibition, a phenomenon characterized by elevated excitatory transmission within the network, and generation of markedly increased activity, such as is observed in epileptiform discharges (31, 32, 33). Although neuromodulators are still active throughout the network, when iGluRs are blocked, the major functional input to GnRH neurons is GABAergic. It could be argued that blockade of iGluRs produces a network that is unbalanced in the direction of inhibition. Although true, this can be viewed as an experimental advantage, because it minimizes, rather than enhances, network interactions within the slice, thus allowing the effects of GABAergic inputs to GnRH neurons to be directly evaluated.
When iGluRs were not blocked, subsequent antagonism of GABAARs resulted in a marked increase in the firing rate in GnRH neurons. Under these recording conditions (i.e. glutamatergic system intact), it is difficult to determine whether this increased firing is due to removal of GABAergic inhibition of GnRH neurons or to enhanced excitation of GnRH neurons by hyperactivated glutamatergic neurons in the brain slice. In contrast, when iGluRs were blocked, antagonism of GABAARs decreased the firing rate. As mentioned above, when iGluRs are blocked, the primary experimental variable is a removal of GABAergic drive. These data thus strongly suggest that endogenous activation of GABAARs can excite GnRH neurons.
Control and PNA females were examined because GABA PSCs are enhanced in PNA mice. The frequency of GABA PSCs in PNA females is twice that in controls (10). This may impact temporal summation of the resulting postsynaptic potentials (PSPs). With more frequent PSPs, the membrane has a greater chance of still being depolarized from a previous PSP, in which case the new PSP will begin from a more depolarized baseline and can result in a greater overall depolarization. In addition, GABAergic PSCs in PNA females are about twice as large as those in control females. Thus, each individual PSP will be larger. In PNA females, both the degree of response of the GnRH neuron and an increased probability of temporal summation may lead to greater stimulatory GABA drive than in diestrous females. This hypothesis is consistent with the present observations that blocking GABAAR in PNA females produced a more profound decrease in the firing rate, and that spontaneous firing occurred in a greater percentage of GnRH neurons from PNA mice.
The present data are also consistent with direct studies of GABA transmission to GnRH neurons in different reproductive states, indicating a direct correlation between GABA drive and GnRH neuron activity. Specifically, progesterone and negative energy balance, two physiological inputs known to reduce GnRH release and GnRH neuron activity (50, 51, 52, 53, 54, 55), reduce both the frequency and the amplitude of GABA PSCs (9, 11, 39). Likewise, prenatal or adult exposure to androgens or leptin administration can increase the activity of GnRH neurons (55) as well as GABA drive (9, 10, 11, 39).
Our previous work measuring elevated intracellular chloride levels in GnRH neurons provided a theoretical basis for the depolarizing/excitatory effects of GABAAR activation. That work also used local, brief application of exogenous GABA to show that excitation can occur. Although exogenous application of GABA may not mimic physiological phenomena, the excitation produced demonstrates that the direction of the membrane potential response to GABAAR activation is depolarizing. Endogenous activation of GABAARs, although of smaller magnitude, would not change the direction of response. Rather, PSPs would become smaller depolarizing potentials.
Of interest in this regard, PSPs that do not reach the threshold for action potential initiation could inhibit firing by reducing the ability of the cell to respond to intrinsic excitatory drives, such as pacemaker potentials, or extrinsic influences, such as synaptic conductances (56, 57). Thus, we do not exclude potential inhibitory actions of GABAAR activation, particularly in conditions where the PSCs are of very low frequency and amplitude, such as under progesterone negative feedback. The inhibition of firing brought about by progesterone may be due to a combination of reduced frequency of a depolarizing input, producing less temporal summation, and a concomitant reduction in the magnitude of the response, so that depolarizations no longer reach the threshold for action potential firing, but, rather, cause depolarizing inhibition. This mechanism may also account for the increase in firing seen in one neuron from experiment 1 of the present study.
The present data are consistent with the hypothesis that the endogenous activation of GABAARs in GnRH neurons is depolarizing and can be excitatory. Factors that regulate the frequency and amount of GABA transmission to GnRH neurons and the responsiveness of the GnRH neuron to GABA (such as progesterone, negative energy balance, and androgens) are poised to push the balance between mere depolarization and excitation one way or the other. As such, both the GABAergic afferent and the postsynaptic response are key factors regulating the reproductive neuroendocrine system.
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Acknowledgments |
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Footnotes |
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A preliminary report of this work was made at the 86th Annual Meeting of The Endocrine Society, New Orleans, LA, June 16–19, 2004 (Abstract P3-264).
First Published Online August 25, 2005
Abbreviations: bic, Bicuculline methiodide; GABA, -aminobutyric acid; GABAAR, type A -aminobutyric acid receptor; iGluR, ionotropic glutamate receptor; NS, normal saline; picro, picrotoxin; PNA, prenatally androgenized; PSC, postsynaptic current; PSP, postsynaptic potential.
Received June 28, 2005.
Accepted for publication August 17, 2005.
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References |
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-aminobutyric acid (GABAA) receptor subunit mRNA expression in postnatal gonadotropin-releasing hormone (GnRH) neurons of the male mouse with single cell RT-PCR. Neuroendocrinology 74:300–308[CrossRef][Medline]
-Aminobutyric acid neurons integrate and rapidly transmit permissive and inhibitory metabolic cues to gonadotropin-releasing hormone neurons. Endocrinology 145:1194–1202-aminobutyric acid and catecholamines in the preoptic/septal area prior to and during the preovulatory surge of luteinizing hormone in the ewe. J Neuroendocrinol 3:393–399
aminobutyric acid and the pubertal increase in luteinizing hormone releasing hormone release in the female rhesus monkeys. J Neuroendocrinol 11:275–282[CrossRef][Medline]
amino butyric acid production near luteinizing hormone-releasing hormone nerve terminals disrupts estrous cyclicity in the rat. Endocrinology 142:2102–2114-aminobutyric acid receptors excites gonadotropin-releasing hormone neurons. Mol Endocrinol 16:2872–2891-amino-3-hydroxy-5-methyl-isoxazolepropionic acid-like inputs in hypothalamic gonadotropin releasing-hormone (GnRH) neurons. Neuroscience 128:443–450[CrossRef][Medline]
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, Greater than 25% decrease in firing rate; 
, no change in firing rate; 
, greater than 25% increase in firing rate.
