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The Journal of Neurophysiology Vol. 87 No. 5 May 2002, pp. 2624-2628
Copyright ©2002 by the American Physiological Society
RAPID COMMUNICATION
1Department of Neurology, UCLA School of Medicine, Los Angeles, California 90095-1769; and 2Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Nusser, Zoltan and
Istvan Mody.
Selective Modulation of Tonic and Phasic Inhibitions in Dentate
Gyrus Granule Cells.
J. Neurophysiol. 87: 2624-2628, 2002.
In some nerve cells, activation of
GABAA receptors by GABA results in phasic and
tonic conductances. Transient activation of synaptic receptors
generates phasic inhibition, whereas tonic inhibition originates from
GABA acting on extrasynaptic receptors, like in cerebellar granule
cells, where it is thought to result from the activation of
extrasynaptic GABAA receptors with a specific subunit composition
(
6
x
). Here we show
that in adult rat hippocampal slices, extracellular GABA levels are
sufficiently high to generate a powerful tonic inhibition in subunit-expressing dentate gyrus granule cells. In these cells, the
mean tonic current is approximately four times larger than that
produced by spontaneous synaptic currents occurring at a frequency of
~10 Hz. Antagonizing the GABA transporter GAT-1 with NO-711 (2.5 µM) selectively enhanced tonic inhibition by 330% without affecting
the phasic component. In contrast, by prolonging the decay of
inhibitory postsynaptic currents (IPSCs), the benzodiazepine agonist
zolpidem (0.5 µM) augmented phasic inhibition by 66%, while leaving
the mean tonic conductance unchanged. These results demonstrate that a
tonic GABAA receptor-mediated conductance can be
recorded from dentate gyrus granule cells of adult rats in in vitro
slice preparations. Furthermore, we have identified distinct
pharmacological tools to selectively modify tonic and phasic
inhibitions, allowing future studies to investigate their specific
roles in neuronal function.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Two types of
GABAA receptor-mediated inhibition have been
described in cerebellar granule cells (Brickley et al.
1996
, 2001; Rossi and Hamann
1998; Wall and Usowicz 1997). Synaptically
released GABA acting on postsynaptic GABAA
receptors produces "phasic" inhibition, whereas "tonic"
inhibition results from the persistent activation of extrasynaptic
receptors by ambient GABA. If tonic inhibition is produced by low
concentrations of ambient GABA thought to be in the low- or
submicromolar range (Attwell et al. 1993), the
extrasynaptic GABAA receptors should have a high
affinity and should not desensitize on the prolonged presence of
agonist. The 6 and subunit-containing receptors expressed by
cerebellar granule cells have such properties (Haas and
Macdonald 1999; Saxena and Macdonald 1994,
1996; Tia et al. 1996) and are
exclusively present extrasynaptically (Nusser et al.
1998). Recent studies, using pharmacological tools demonstrated
that these receptors can be activated by an overspill of synaptically
released GABA (Rossi and Hamann 1998), while experiments
with knock-out animals (Brickley et al. 2001) have
conclusively shown their role in the generation of tonic inhibition in
cerebellar granule cells.
There is little known about the presence of tonic inhibition in other
cell types of the mammalian CNS, although in some cells, differences
between the properties of synaptic and extrasynaptic receptors have
been reported (Bai et al. 2001; Banks and Pearce 2000). Of the two GABAA receptor subunits
involved in mediating tonic inhibition in cerebellar granule cells, the
6 subunit has a very restricted distribution (granule cells of the
cerebellum and dorsal cochlear nucleus), while the subunit is
widespread in the CNS (Fritschy and Mohler 1995;
Wisden et al. 1992). In the forebrain, the subunit
mainly forms functional GABAA receptors with 4
and subunits (Sieghart 1995; Sur et al.
1999). Such receptors may underlie tonic inhibition in many
brain regions if their properties and subcellular distributions
are comparable with those of cerebellar
6x receptors. In
the present study, we investigated whether tonic inhibition could be
detected in subunit-expressing dentate gyrus granule cells in
acute in vitro brain slices obtained from adult rats. Provided tonic
inhibition is found in this cell type, we also aimed to develop
specific pharmacological tools to selectively modulate the two types of inhibition.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Slice preparation and in vitro electrophysiological recordings
Thirteen adult (>3 mo old) Wistar rats were anesthetized with
Na-pentobarbital (70 mg/kg ip) in accordance with an animal protocol
approved by the UCLA Chancellor's ARC. After decapitation, the brains
were removed and placed into an ice-cold artificial cerebrospinal fluid
(ACSF) containing (in mM) 126 NaCl, 2.5 KCl, 2 CaCl2, 2 MgCl2, 1.25 NaH2PO4, 26 NaHCO3, and 10 D-glucose, pH 7.3 when
bubbled with 95% O2-5%
CO2. Coronal slices (300-350 µm in thickness)
were cut with a vibratome (Leica VT1000S) and were stored at 32°C
until they were transferred to the recording chamber. During
recordings, the slices were continuously perfused with 34-36°C ACSF
containing 3-5 mM kynurenic acid (Sigma). All recordings were made
from the somata of visually identified neurons (Zeiss Axioscope and
Leica DMS IR-DIC videomicroscopy, ×40 water immersion objective) with
an Axopatch 200B amplifier (Axon Instruments, Foster City, CA). Patch
electrodes were filled with a solution containing (in mM) 140 CsCl, 4 NaCl, 1 MgCl2, 10 HEPES, 0.05 EGTA, 2 Mg-ATP, and
0.4 Mg-GTP. The intracellular solution was titrated to a pH of 7.25 and
to an osmolarity of 280-290 mosmol. The DC resistance of the
electrodes was 4-8 M
when filled with the pipette solution. Series
resistance (Rs) and whole cell
capacitance were estimated by compensating for the fast current
transients evoked at the onset and offset of 8-ms, 5-mV voltage-command
steps. The Rs was either
uncompensated or compensated by 75-80% (with 7- to 8-µs lag
values). Uncompensated Rs was
16.6 ± 7.2 M (mean ± SD).
To identify GABAA receptor-mediated currents, 10-30 µl of 20 mM aqueous solution of bicuculline methiodide (BMI, Sigma; for 16 cells) or SR95531 (Sigma; for 3 cells) was directly injected into the recording chamber where it rapidly mixed with the perfusate. Considering the volume of the chamber (~2 ml) and the flow rate (2.5 ml/min) of the ACSF, the final concentrations of BMI or of SR95531 were estimated to be between 100 and 150 µM.
Data analysis
All recordings were low-pass filtered at 2 kHz and digitized
on-line at 20 kHz. The inhibitory postsynaptic currents (IPSCs) were
detected and analyzed as described previously (Nusser et al.
2001). The mean phasic current was calculated by multiplying the charge of the averaged spontaneous, GABAA
receptor
mediated IPSC (sIPSC) with the sIPSC frequency. The
frequency, charge per IPSC and the mean phasic current were compared
between different experimental conditions using the unpaired
t-test assuming unequal variances.
The baseline current was measured as follows. The mean of a 5-ms epoch
taken every 100 ms served as one data point. By taking the mean of 100 baseline points over 5 ms (at 20-kHz sampling rate) allowed us to
average out any high-frequency noise from the records. Baseline points
falling on to the decay of IPSCs were discarded from the analysis. Such
baseline points were usually identified from an increased SD of the
5-ms epoch. The mean and SD of the averaged baseline points were
calculated for 10 s (~100 averaged baseline points) at three
distinct times of the recordings (periods a,
b, and c; see Fig.
1C). The time separation (30 s) between periods a and b was always
the same as that between b and c. Another method
was also developed to quantify the mean tonic current. In this method,
the baseline was calculated by generating all-point histograms of 10-s
epochs at periods a, b, and
c (see Fig. 1D), and a Gaussian distribution was
fitted to the histogram at period c, or single
Gaussians were fitted to the positive side of the all-point histograms
at periods a and b. The differences between the
means of the fitted Gaussians at periods a and b
and periods b and c were then calculated. As both methods of baseline calculation provided practically identical results,
we decided to employ the first method in this study. Two changes in the
baseline current were calculated between the three periods. The first
(
BL1), reflecting the time-dependent fluctuations in the baseline,
was the absolute (i.e., ignoring the sign) value of the
baseline difference during recording periods a and
b (see black column in Fig. 3D). The second
(BL2), reflecting the effect of the GABAA
receptor antagonist, was obtained from the absolute (i.e.,
ignoring the sign) value of the baseline difference during recording
periods c and b. The two baseline
changes (BL1 and BL2) were then statistically compared (paired
t-test) in each cell.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested whether tonic inhibition could be detected in 4/
subunit-expressing dentate gyrus granule cells by obtaining whole cell
voltage-clamp recordings in in vitro acute slices from adult rats.
sIPSCs were readily observed. By measuring the charge carried by the
averaged sIPSCs and the frequency of the sIPSCs, the mean phasic
current could be calculated and compared between different experimental
conditions. To obtain an objective measure of the mean tonic current,
we used a method based on measuring the change in baseline current
following the application of a GABAA receptor antagonist (see Fig. 1 and METHODS).
The application of ~100 µM SR95531 or BMI resulted in the complete
disappearance of sIPSCs (Fig.
2B) and an outward shift in
the baseline current (Figs. 1 and 2A). The value of BL2
(12.8 ± 3.0 pA, mean ± SE; n = 5) was
significantly larger (P < 0.05, paired
t-test) than BL1 (3.9 ± 1.3 pA, n = 5), showing that the change in baseline was indeed due to the
effect of the antagonist (Figs. 2 and 3).
The mean phasic current (2.4 ± 0.6 pA, n = 9) calculated from the sIPSC frequency (10.1 ± 2.1 Hz,
n = 9) and from the charge carried by the average
sIPSCs (0.23 ± 0.04 pC, n = 9) was around 25% of
the mean tonic current under control conditions. These results
demonstrate that 4/ subunit-expressing adult rat dentate granule
cells display a significant amount of tonic inhibition that is almost
four times larger than that mediated by sIPSCs occurring at ~10 Hz.
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Next we sought to increase the concentration of ambient GABA by
antagonizing GABA uptake using 2.5 µM of the nonsubstrate GAT-1
inhibitor NO711 (Borden et al. 1994), and to investigate its effect on phasic and tonic GABAA
receptor-mediated currents. The drug produced no significant change in
the charge (0.21 ± 0.01 pC, n = 5 in NO711) and
frequency (11.0 ± 3.7 Hz, n = 5 in NO711) of
sIPSCs (Figs. 2 and 3). Consequently, the mean phasic current (2.3 ± 0.8 pA, n = 5 in NO711) was unaffected by NO711. Concomitantly, however, there was an almost fourfold increase in the
mean tonic current (47.6 ± 10.1 pA, n = 7, P < 0.01 unpaired t-test) compared with control.
Following the specific increase in the tonic current by NO711, we aimed
to augment the phasic current independently of the tonic conductance.
If the tonic current is mediated by 4 or 4
2 receptors
in granule cells, this current should be insensitive to benzodiazepine
agonists (Sieghart 1995), whereas synaptic currents are
known to be sensitive to zolpidem, a benzodiazepine agonist (Hajos et al. 2000). In agreement with our prediction,
0.5 µM zolpidem did not alter the mean tonic current
(P > 0.05 compared with control, Figs. 2 and 3), but
increased the mean phasic current (3.9 ± 0.2 pA,
n = 3) by 66% through the prolongation of sIPSC decays
without affecting their frequency (10.8 ± 1.0 Hz,
n = 3). These results demonstrate that tonic and phasic
inhibitions in adult rat dentate gyrus granule cells can be selectively
increased by a GABA uptake inhibitor and by a benzodiazepine agonist, respectively.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A considerable amount of tonic current was present in the 4/
subunit-expressing adult rat dentate gyrus granule cells, which was
approximately four times larger than the total synaptic (phasic) current even when the frequency of spontaneous IPSCs was ~10 Hz. The
differential sensitivities of the two types of inhibition to the
benzodiazepine agonist zolpidem in these cells is consistent with
different GABAA receptor subtypes mediating the
two conductances. Furthermore, the selective fourfold increase of the
tonic inhibition on blocking the GABA transporter GAT-1 indicates that
the tonic conductance is under the control of a powerful GABA uptake.
Powerful GABA uptake regulates tonic inhibition
It has been known for some time that GABA uptake can shape the
decay of synaptic currents (Dingledine and Korn 1985;
Korn and Dingledine 1986; Roepstorff and Lambert
1992; Thompson and Gahwiler 1992) and that it
can regulate GABAergic signaling at both GABAA
and GABAB receptors relatively distant from the
release site (Isaacson et al. 1993). Our study
demonstrated that, most likely through the GAT-1 GABA transporter, the
GABA uptake system has a much more profound influence on tonic than on
phasic inhibition in adult dentate gyrus granule cells. Similar results
were obtained recently in postnatal day 6-18
(P6-P18) rat CA1 neurons, where ramp depolarizations
exposed merely a leak conductance unless the GABA uptake inhibitor
tiagabine was added to the perfusate (Frahm et al.
2001). It appears that at near physiological temperatures in
acute brain slice preparations, GABA uptake may keep the ambient GABA
concentration sufficiently low to prevent the activation of
GABAA receptors or to allow that of only a
specific subsets of receptors (high affinity, nondesensitizing).
Clearly, a slice preparation continuously washed with ACSF may not
necessarily reflect the conditions for GABA uptake in the intact brain
or that in other biochemical preparations (Wood and Sidhu
1986). Nevertheless, our finding that GABA uptake predominantly
regulates the amount of tonic GABAA
receptor-mediated current may have significant consequences on the
regulation of cellular and integrative properties of nerve cells.
In general, functional consequences of the tonic inhibition are not
well understood. One of its possible roles could be to set the membrane
potential close to the reversal potential
(EGABA) of GABA-induced currents,
allowing an ambient GABA concentration-dependent regulation of the
membrane potential. In dentate gyrus granule cells this results in a
steady depolarization as EGABA is
about 15 mV positive to the resting membrane potential (Soltesz
and Mody 1994). The amount of this depolarization would be a
function of the ambient GABA, reflecting the overall network activity, particularly that of the GABA releasing neurons. In contrast to its
action on the tonic current under our experimental conditions, inhibition of GABA uptake had no significant effect on the mean phasic
current. The reason for this may be a dual consequence of the uptake
inhibition. The resulting elevated ambient GABA concentration may have
induced a small steady-state desensitization of the synaptic receptors
(Overstreet et al. 2000), thus reducing the
amplitude and the charge of the IPSCs. At the same time, the slowed GABA clearance may have prolonged the decay of the IPSCs (Williams et al. 1998), consequently increasing the
charge transfer during synaptic events. These two effects of GABA
uptake inhibition, decreasing and increasing the total charge per IPSC,
may have canceled each other out, leaving the mean phasic current unaffected.
Tonic and phasic inhibitions are mediated by distinct GABAA receptor subtypes
In cerebellar granule cells, where tonic inhibition was first
described, distinct GABAA receptor subtypes
mediate tonic and phasic inhibitions. Our results with zolpidem also
indicate that in dentate gyrus granule cells, 4 subunit-containing
receptors could be primarily responsible for the tonic inhibition. In
this cell type, 4x
and
4x2
subunit-containing receptors (Bencsits et al. 1999) may
be exclusively present extrasynaptically, and they may have a high
affinity for GABA and may not desensitize on the prolonged presence of
agonist. Phasic inhibition is likely to be mediated by
1x2
or
2x2
receptors, as the synaptic currents are known to be benzodiazepine
sensitive (De Koninck and Mody 1994; Hajos et al.
2000; Otis and Mody 1992). Although high-resolution anatomical studies are presently lacking in dentate granule cells, the 4 subunit-containing receptors may be confined to extrasynaptic sites just like the
6x receptors of
cerebellar granule cells (Nusser et al. 1998). Another
pharmacological difference between the sensitivities of tonic and
phasic inhibitions to two competitive GABAA
receptor antagonists has been recently reported by Bai et al.
(2001) in CA1 pyramidal cells. In contrast to this study, we
did not find any difference in dentate gyrus granule cells between the
two antagonists, albeit at higher concentrations, in their ability to
block tonic and phasic inhibitions. The discovery of specific
pharmacological tools allowing the modulation of one type of inhibition
independently of the other will be extremely useful for elucidating
their roles in the control of neuronal excitability.
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ACKNOWLEDGMENTS |
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This work was supported by grants from the Wellcome Trust and from the Boehringer Ingelheim Fond to Z. Nusser, National Institute of Neurological Disorders and Stroke Grant NS-30549 and the Coelho Endowment to I. Mody, and a grant from the James S. McDonnell Foundation to Z. Nusser and I. Mody.
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FOOTNOTES |
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Address for reprint requests: Z. Nusser, Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony Street 43, 1083 Budapest, Hungary (E-mail: nusser{at}koki.hu).
Received 22 October 2001; accepted in final form 27 December 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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R. L. Fleming, W. A. Wilson, and H. S. Swartzwelder Magnitude and Ethanol Sensitivity of Tonic GABAA Receptor-Mediated Inhibition in Dentate Gyrus Changes From Adolescence to Adulthood J Neurophysiol, May 1, 2007; 97(5): 3806 - 3811. [Abstract] [Full Text] [PDF]
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D. P. Bright, M. I. Aller, and S. G. Brickley Synaptic Release Generates a Tonic GABAA Receptor-Mediated Conductance That Modulates Burst Precision in Thalamic Relay Neurons J. Neurosci., March 7, 2007; 27(10): 2560 - 2569. [Abstract] [Full Text] [PDF]
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K. R. Drasbek, K. Hoestgaard-Jensen, and K. Jensen Modulation of Extrasynaptic THIP Conductances by GABAA-Receptor Modulators in Mouse Neocortex J Neurophysiol, March 1, 2007; 97(3): 2293 - 2300. [Abstract] [Full Text] [PDF]
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J. Maguire and I. Mody Neurosteroid Synthesis-Mediated Regulation of GABAA Receptors: Relevance to the Ovarian Cycle and Stress J. Neurosci., February 28, 2007; 27(9): 2155 - 2162. [Abstract] [Full Text] [PDF]
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A. H. Lagrange, E. J. Botzolakis, and R. L. Macdonald Enhanced macroscopic desensitization shapes the response of {alpha}4 subtype-containing GABAA receptors to synaptic and extrasynaptic GABA J. Physiol., February 1, 2007; 578(3): 655 - 676. [Abstract] [Full Text] [PDF]
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H. Alle and J. R. P. Geiger GABAergic Spill-Over Transmission onto Hippocampal Mossy Fiber Boutons J. Neurosci., January 24, 2007; 27(4): 942 - 950. [Abstract] [Full Text] [PDF]
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E. Gascon, A. G. Dayer, M.-O. Sauvain, G. Potter, B. Jenny, M. De Roo, E. Zgraggen, N. Demaurex, D. Muller, and J. Z. Kiss GABA Regulates Dendritic Growth by Stabilizing Lamellipodia in Newly Generated Interneurons of the Olfactory Bulb J. Neurosci., December 13, 2006; 26(50): 12956 - 12966. [Abstract] [Full Text] [PDF]
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E. Bouairi, H. Kamendi, X. Wang, C. Gorini, and D. Mendelowitz Multiple Types of GABAA Receptors Mediate Inhibition in Brain Stem Parasympathetic Cardiac Neurons In the Nucleus Ambiguus J Neurophysiol, December 1, 2006; 96(6): 3266 - 3272. [Abstract] [Full Text] [PDF]
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J.-s. Qi, J. Yao, C. Fang, B. Luscher, and G. Chen Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures J. Physiol., December 1, 2006; 577(2): 579 - 590. [Abstract] [Full Text] [PDF]
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Y. Wu, W. Wang, and G. B. Richerson The Transmembrane Sodium Gradient Influences Ambient GABA Concentration by Altering the Equilibrium of GABA Transporters J Neurophysiol, November 1, 2006; 96(5): 2425 - 2436. [Abstract] [Full Text] [PDF]
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 D. Chandra, F. Jia, J. Liang, Z. Peng, A. Suryanarayanan, D. F. Werner, I. Spigelman, C. R. Houser, R. W. Olsen, N. L. Harrison, et al. GABAA receptor {alpha}4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol PNAS, October 10, 2006; 103(41): 15230 - 15235. [Abstract] [Full Text] [PDF]
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 J. H. Krystal, J. Staley, G. Mason, I. L. Petrakis, J. Kaufman, R. A. Harris, J. Gelernter, and J. Lappalainen {gamma}-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment. Arch Gen Psychiatry, September 1, 2006; 63(9): 957 - 968. [Abstract] [Full Text] [PDF]
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H. L. Payne, P. S. Donoghue, W. M. K. Connelly, S. Hinterreiter, P. Tiwari, J. H. Ives, V. Hann, W. Sieghart, G. Lees, and C. L. Thompson Aberrant GABAA Receptor Expression in the Dentate Gyrus of the Epileptic Mutant Mouse Stargazer. J. Neurosci., August 15, 2006; 26(33): 8600 - 8608. [Abstract] [Full Text] [PDF]
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G. A. Prenosil, E. M. Schneider Gasser, U. Rudolph, R. Keist, J.-M. Fritschy, and K. E. Vogt Specific Subtypes of GABAA Receptors Mediate Phasic and Tonic Forms of Inhibition in Hippocampal Pyramidal Neurons J Neurophysiol, August 1, 2006; 96(2): 846 - 857. [Abstract] [Full Text] [PDF]
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 J. B. Park, S. Skalska, and J. E. Stern Characterization of a Novel Tonic {gamma}-Aminobutyric AcidA Receptor-Mediated Inhibition in Magnocellular Neurosecretory Neurons and Its Modulation by Glia Endocrinology, August 1, 2006; 147(8): 3746 - 3760. [Abstract] [Full Text] [PDF]
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K. R. Drasbek and K. Jensen THIP, a Hypnotic and Antinociceptive Drug, Enhances an Extrasynaptic GABAA Receptor-mediated Conductance in Mouse Neocortex Cereb Cortex, August 1, 2006; 16(8): 1134 - 1141. [Abstract] [Full Text] [PDF]
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C. Hull, G.-L. Li, and H. von Gersdorff GABA transporters regulate a standing GABAC receptor-mediated current at a retinal presynaptic terminal. J. Neurosci., June 28, 2006; 26(26): 6979 - 6984. [Abstract] [Full Text] [PDF]
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M. Wallner, H. J. Hanchar, and R. W. Olsen From the Cover: Low-dose alcohol actions on {alpha}4beta3{delta} GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513 PNAS, May 30, 2006; 103(22): 8540 - 8545. [Abstract] [Full Text] [PDF]
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J. Glykys and I. Mody Hippocampal Network Hyperactivity After Selective Reduction of Tonic Inhibition in GABAA Receptor {alpha}5 Subunit-Deficient Mice J Neurophysiol, May 1, 2006; 95(5): 2796 - 2807. [Abstract] [Full Text] [PDF]
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K. Kirmse and S. Kirischuk Ambient GABA constrains the strength of GABAergic synapses at Cajal-Retzius cells in the developing visual cortex. J. Neurosci., April 19, 2006; 26(16): 4216 - 4227. [Abstract] [Full Text] [PDF]
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E. D. Eggers and P. D. Lukasiewicz GABAA, GABAC and glycine receptor-mediated inhibition differentially affects light-evoked signalling from mouse retinal rod bipolar cells J. Physiol., April 1, 2006; 572(1): 215 - 225. [Abstract] [Full Text] [PDF]
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V. Santhakumar, H. J. Hanchar, M. Wallner, R. W. Olsen, and T. S. Otis Contributions of the GABAA receptor alpha6 subunit to phasic and tonic inhibition revealed by a naturally occurring polymorphism in the alpha6 gene. J. Neurosci., March 22, 2006; 26(12): 3357 - 3364. [Abstract] [Full Text] [PDF]
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C. M. Borghese, S. i Storustovu, B. Ebert, M. B. Herd, D. Belelli, J. J. Lambert, G. Marshall, K. A. Wafford, and R. A. Harris The {delta} Subunit of {gamma}-Aminobutyric Acid Type A Receptors Does Not Confer Sensitivity to Low Concentrations of Ethanol J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1360 - 1368. [Abstract] [Full Text] [PDF]
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Z. Mtchedlishvili and J. Kapur High-Affinity, Slowly Desensitizing GABAA Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells Mol. Pharmacol., February 1, 2006; 69(2): 564 - 575. [Abstract] [Full Text] [PDF]
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F. Jia, L. Pignataro, C. M. Schofield, M. Yue, N. L. Harrison, and P. A. Goldstein An Extrasynaptic GABAA Receptor Mediates Tonic Inhibition in Thalamic VB Neurons J Neurophysiol, December 1, 2005; 94(6): 4491 - 4501. [Abstract] [Full Text] [PDF]
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G. A. Kinney GAT-3 Transporters Regulate Inhibition in the Neocortex J Neurophysiol, December 1, 2005; 94(6): 4533 - 4537. [Abstract] [Full Text] [PDF]
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A. Scimemi, A. Semyanov, G. Sperk, D. M. Kullmann, and M. C. Walker Multiple and Plastic Receptors Mediate Tonic GABAA Receptor Currents in the Hippocampus J. Neurosci., October 26, 2005; 25(43): 10016 - 10024. [Abstract] [Full Text] [PDF]
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S. Keros and J. J. Hablitz Subtype-Specific GABA Transporter Antagonists Synergistically Modulate Phasic and Tonic GABAA Conductances in Rat Neocortex J Neurophysiol, September 1, 2005; 94(3): 2073 - 2085. [Abstract] [Full Text] [PDF]
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N. E. Hallworth and M. D. Bevan Globus Pallidus Neurons Dynamically Regulate the Activity Pattern of Subthalamic Nucleus Neurons through the Frequency-Dependent Activation of Postsynaptic GABAA and GABAB Receptors J. Neurosci., July 6, 2005; 25(27): 6304 - 6315. [Abstract] [Full Text] [PDF]
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S. S Smith and Q. H. Gong Neurosteroid administration and withdrawal alter GABAA receptor kinetics in CA1 hippocampus of female rats J. Physiol., April 15, 2005; 564(2): 421 - 436. [Abstract] [Full Text] [PDF]
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D. Gonzalez-Forero and F. J. Alvarez Differential Postnatal Maturation of GABAA, Glycine Receptor, and Mixed Synaptic Currents in Renshaw Cells and Ventral Spinal Interneurons J. Neurosci., February 23, 2005; 25(8): 2010 - 2023. [Abstract] [Full Text] [PDF]
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I. Mody Aspects of the homeostaic plasticity of GABAA receptor-mediated inhibition J. Physiol., January 1, 2005; 562(1): 37 - 46. [Abstract] [Full Text] [PDF]
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E. M. Petrini, I. Marchionni, P. Zacchi, W. Sieghart, and E. Cherubini Clustering of Extrasynaptic GABAA Receptors Modulates Tonic Inhibition in Cultured Hippocampal Neurons J. Biol. Chem., October 29, 2004; 279(44): 45833 - 45843. [Abstract] [Full Text] [PDF]
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W. Wei, L. C. Faria, and I. Mody Low Ethanol Concentrations Selectively Augment the Tonic Inhibition Mediated by {delta} Subunit-Containing GABAA Receptors in Hippocampal Neurons J. Neurosci., September 22, 2004; 24(38): 8379 - 8382. [Abstract] [Full Text] [PDF]
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S. K. Towers, T. Gloveli, R. D. Traub, J. E. Driver, D. Engel, R. Fradley, T. W. Rosahl, K. Maubach, T. L. E. H. Buhl, and M. A. Whittington {alpha}5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro J. Physiol., September 15, 2004; 559(3): 721 - 728. [Abstract] [Full Text] [PDF]
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M. C. Bieda and M. B. MacIver Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability J Neurophysiol, September 1, 2004; 92(3): 1658 - 1667. [Abstract] [Full Text] [PDF]
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J. Liang, E. Cagetti, R. W. Olsen, and I. Spigelman Altered Pharmacology of Synaptic and Extrasynaptic GABAA Receptors on CA1 Hippocampal Neurons Is Consistent with Subunit Changes in a Model of Alcohol Withdrawal and Dependence J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1234 - 1245. [Abstract] [Full Text] [PDF]
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H.-J. Shu, L. N. Eisenman, D. Jinadasa, D. F. Covey, C. F. Zorumski, and S. Mennerick Slow Actions of Neuroactive Steroids at GABAA Receptors J. Neurosci., July 28, 2004; 24(30): 6667 - 6675. [Abstract] [Full Text] [PDF]
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C. van Rijnsoever, M. Tauber, M. K. Choulli, R. Keist, U. Rudolph, H. Mohler, J. M. Fritschy, and F. Crestani Requirement of {alpha}5-GABAA Receptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice J. Neurosci., July 28, 2004; 24(30): 6785 - 6790. [Abstract] [Full Text] [PDF]
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S. Sipila, K. Huttu, J. Voipio, and K. Kaila GABA Uptake via GABA Transporter-1 Modulates GABAergic Transmission in the Immature Hippocampus J. Neurosci., June 30, 2004; 24(26): 5877 - 5880. [Abstract] [Full Text] [PDF]
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G. Akk, J. Bracamontes, and J. H. Steinbach Activation of GABAA receptors containing the {alpha}4 subunit by GABA and pentobarbital J. Physiol., April 15, 2004; 556(2): 387 - 399. [Abstract] [Full Text] [PDF]
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M. Wallner, H. J. Hanchar, and R. W. Olsen From The Cover: Ethanol enhances {alpha}4{beta}3{delta} and {alpha}6{beta}3{delta} {gamma}-aminobutyric acid type A receptors at low concentrations known to affect humans PNAS, December 9, 2003; 100(25): 15218 - 15223. [Abstract] [Full Text] [PDF]
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B. M. Stell, S. G. Brickley, C. Y. Tang, M. Farrant, and I. Mody Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by {delta} subunit-containing GABAA receptors PNAS, November 25, 2003; 100(24): 14439 - 14444. [Abstract] [Full Text] [PDF]
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W. Wei, N. Zhang, Z. Peng, C. R. Houser, and I. Mody Perisynaptic Localization of {delta} Subunit-Containing GABAA Receptors and Their Activation by GABA Spillover in the Mouse Dentate Gyrus J. Neurosci., November 19, 2003; 23(33): 10650 - 10661. [Abstract] [Full Text] [PDF]
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D. Belelli and M. B. Herd The Contraceptive Agent Provera Enhances GABAA Receptor-Mediated Inhibitory Neurotransmission in the Rat Hippocampus: Evidence for Endogenous Neurosteroids? J. Neurosci., November 5, 2003; 23(31): 10013 - 10020. [Abstract] [Full Text] [PDF]
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K. Jensen, C.-S. Chiu, I. Sokolova, H. A. Lester, and I. Mody GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus J Neurophysiol, October 1, 2003; 90(4): 2690 - 2701. [Abstract] [Full Text] [PDF]
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G. B. Richerson and Y. Wu Dynamic Equilibrium of Neurotransmitter Transporters: Not Just for Reuptake Anymore J Neurophysiol, September 1, 2003; 90(3): 1363 - 1374. [Abstract] [Full Text] [PDF]
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Y. Iwai, M. Fagiolini, K. Obata, and T. K. Hensch Rapid Critical Period Induction by Tonic Inhibition in Visual Cortex J. Neurosci., July 30, 2003; 23(17): 6695 - 6702. [Abstract] [Full Text] [PDF]
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Y. Wu, W. Wang, and G. B. Richerson Vigabatrin Induces Tonic Inhibition Via GABA Transporter Reversal Without Increasing Vesicular GABA Release J Neurophysiol, April 1, 2003; 89(4): 2021 - 2034. [Abstract] [Full Text] [PDF]
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L. S. Overstreet and G. L. Westbrook Synapse Density Regulates Independence at Unitary Inhibitory Synapses J. Neurosci., April 1, 2003; 23(7): 2618 - 2626. [Abstract] [Full Text] [PDF]
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F.-C. Hsu and S. S. Smith Progesterone Withdrawal Reduces Paired-Pulse Inhibition in Rat Hippocampus: Dependence on GABAA Receptor alpha 4 Subunit Upregulation J Neurophysiol, January 1, 2003; 89(1): 186 - 198. [Abstract] [Full Text] [PDF]
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J. Y. T. Yeung, K. J. Canning, G. Zhu, P. Pennefather, J. F. MacDonald, and B. A. Orser Tonically Activated GABAA Receptors in Hippocampal Neurons Are High-Affinity, Low-Conductance Sensors for Extracellular GABA Mol. Pharmacol., January 1, 2003; 63(1): 2 - 8. [Abstract] [Full Text] [PDF]
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