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The Journal of Neurophysiology Vol. 83 No. 5 May 2000, pp. 3169-3172
Copyright ©2000 by the American Physiological Society
RAPID COMMUNICATION
1Medical Research Council Anatomical Neuropharmacology Unit, University Department of Pharmacology, Oxford OX1 3TH, United Kingdom; 2Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee 38163; and 3Division of Life Science, University of Texas, San Antonio, Texas 78294
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Bevan, Mark D., Charles J. Wilson, J. Paul Bolam, and Peter J. Magill. Equilibrium Potential of GABAA Current and Implications for Rebound Burst Firing in Rat Subthalamic Neurons In Vitro. J. Neurophysiol. 83: 3169-3172, 2000. Reciprocally connected glutamatergic subthalamic and GABAergic globus pallidus neurons have recently been proposed to act as a generator of low-frequency oscillatory activity in Parkinson's disease. To determine whether GABAA receptor-mediated synaptic potentials could theoretically generate rebound burst firing in subthalamic neurons, a feature that is central to the proposed oscillatory mechanism, we determined the equilibrium potential of GABAA current (EGABAA) and the degree of hyperpolarization required for rebound firing using perforated-patch recording. In the majority of neurons that fired rebounds, EGABAA was equal to or more hyperpolarized than the hyperpolarization required for rebound burst firing. These data suggest that synchronous activity of pallidal inputs could underlie rhythmic bursting activity of subthalamic neurons in Parkinson's disease.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subthalamic neurons possess an intrinsic pacemaker
mechanism which underlies their rhythmic discharge in vitro and their
function as a driving force of neuronal activity in the basal ganglia
in vivo (Bevan and Wilson 1999
). Removal of
hyperpolarizing current can produce a rebound depolarization and a
burst of firing in subthalamic neurons (Nakanishi et al.
1987). Rebound excitations of this type do not play a role in
the spontaneous rhythmic firing of subthalamic neurons because the
necessary degree of hyperpolarization is not attained during the
afterhyperpolarization from a single action potential (Bevan and
Wilson 1999). Rhythmic bursting activity of subthalamic neurons
is phase-related to resting tremor in idiopathic and animal models of
Parkinson's disease (Bergman et al. 1994; Rodriguez et al. 1998) and has been suggested to arise
from interactions with reciprocally connected GABAergic neurons of the
globus pallidus through a mechanism that is similar to that reported
for thalamic nuclei (McCormick and Bal 1997;
Plenz and Kitai 1999). The aim of this study was to test
whether GABAA current could generate sufficient
hyperpolarization in subthalamic neurons to produce rebound burst
firing. Thus we determined
EGABAA and the
hyperpolarization required for rebound burst firing in subthalamic
neurons using perforated-patch recording. We used the cation selective
pore-forming substance gramicidin to maintain a natural intracellular
concentration of chloride, the major permeant ion of the
GABAA receptor (Ulrich and Huguenard
1997).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Slice preparation and visualized recording
Coronal slices (300-µm thickness) of the subthalamus were
prepared from male Sprague-Dawley rats (16- to 23-day old) as described previously (Bevan and Wilson 1999). Individual slices
were transferred to a recording chamber, perfused with ACSF at 30-32
or 35-37°C and were examined using infrared differential
interference contrast video microscopy (Infrapatch Workstation, Luigs
and Neumann, Ratingen, Germany). Somatic recordings were made using
patch pipettes prepared from thick-wall borosilicate glass and filled
with a solution containing (in mM) 106 K-MeSO4,
25 KCl, 1 MgCl2.6H2O, 0.1 CaCl2.2H20, 10 HEPES, and 1 EGTA, pH, 7.3; osmolarity, 290-300 mosmol. Gramicidin was added to the
intracellular solution at a concentration of 5 µg/ml. Resistance of
the filled pipettes ranged from 3 to 6 M
. Fast capacitative
transients of the pipette were nulled on-line but voltage errors due to
series resistance were compensated off-line. Recordings were made in
the perforated and whole-cell configurations using an EPC 9/2. C
amplifier (HEKA, Lambrecht, Germany) and Pulse 8.3 (HEKA). Signals were
low-pass filtered at a frequency (1.7-33.3 kHz) that was three times
less the frequency of digitization (5-100 kHz).
Measurement of EGABAA
Pressure pulses of GABA (100 µM in the pipette) were directed
at the soma of recorded neurons (Fig.
1A). The selective
GABAB antagonist CGP 55845A (10 µM; supplied by
Novartis) was bath applied at a concentration that saturated
GABAB receptors. Responses were recorded at
various holding potentials in current- and voltage-clamp modes. Changes
in holding potential were made between 800 and 1,000 ms before the GABA
spritz to allow the membrane potential to reach its steady-state value.
In current clamp, EGABAA
was measured as the potential at which GABA evoked no response or as
the mean of the two voltages at which the smallest depolarizing and
hyperpolarizing responses were evoked. In voltage clamp,
EGABAA was taken as the
intersection of peak GABA current and baseline current plotted against
voltage. Baseline current was measured as the current flowing at the
same time as the peak GABA response by repeating the protocol in the
absence of GABA and/or by extrapolation from monoexponential fits of
currents flowing before and after the GABA response. Voltages errors
were corrected according to the equation
Vcorrected = Vcommand 
(I × Rseries).
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Measurement of hyperpolarization required for rebound burst firing
Injections of varying amounts of hyperpolarizing current were made for 500 ms and the maximum degree of hyperpolarization during a pulse was measured. A "rebound burst" after removal of negative current was defined as a burst that contained one or more intervals that were at least three times shorter than those associated with spontaneous activity. The threshold for rebound burst firing was defined as the minimum value of peak hyperpolarization that preceded a rebound burst.
Statistical comparisons were made using the Mann-Whitney U test. Probability values of <0.05 were considered significant. Data are expressed as means ± SD.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Stable series resistances of between 25 and 75 M were obtained
40-60 min after sealing.
EGABAA was determined
using current clamp (78 ± 5 mV, n = 20) and in
most cases also using voltage clamp (78 ± 4 mV,
n = 15). Similar values were obtained with the two
techniques (P = 0.85), and the difference in
EGABAA in individual
neurons was small (2 ± 1 mV, n = 15). The
whole-cell configuration was established after perforated recording in
six cells. In these cases,
EGABAA
shifted significantly toward more positive values (Fig. 1, B
and C: P = 0.004; 77 ± 6 mV,
perforated; 52 mV ± 6 mV, whole-cell) predicted by the Nernst
equation (42 mV). This observation confirmed that
EGABAA was measured using the perforated configuration.
EGABAA was not altered by
the application of the carbonic anhydrase inhibitor ethoxyzolamide
(P = 0.58; 77 ± 6 mV, n = 6, control; 79 ± 5 mV, n = 6, ethoxyzolamide); this suggests that neurons were not chloride-loaded by the protocol and
EGABAA was dominated by
chloride gradient (Staley et al. 1995). The response of
subthalamic neurons to GABA were due solely to actions at
GABAA receptors because the
GABAA antagonist bicuculline (30 µM) abolished
responses (n = 4).
Rebound burst firing was observed in 17 of 20 neurons (Figs.
2 and 3).
The threshold for rebound bursts was 78 ± 3 mV
(n = 17). Neurons fired either short (Figs. 2,
A and C, and 3D, n = 12) or long duration bursts (Fig. 2B, n = 5). EGABAA was equal to,
or more negative than, the threshold for rebound burst firing in 14 of
the 17 neurons that fired rebound bursts (Fig. 3).
EGABAA and burst
thresholds were not significantly different at the two recording
temperatures (EGABAA:
P = 0.25; 77 ± 5 mV, n = 11, 30-32°C; 80 ± 4 mV, n = 9, 35-37°C. Burst
threshold: P = 0.34; 78 ± 3 mV,
n = 11, 30-32°C; 77 ± 3 mV,
n = 6, 35-37°C).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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These data suggest that
EGABAA in subthalamic
neurons is sufficiently hyperpolarized for GABAA
receptor-mediated synaptic potentials to produce rebound burst firing.
The value of EGABAA and
the magnitude and duration of hyperpolarization required for burst
firing suggest that sufficient hyperpolarization could only be
generated by synchronous barrages of GABAergic synaptic potentials. During normal movement, sufficient hyperpolarization is unlikely to
occur as subthalamic and pallidal neurons discharge asynchronously in
an irregular single spike or burst mode (Nini et al.
1995; Wichmann et al. 1994). Under these
conditions, it is likely that burst firing of subthalamic neurons is
generated by excitatory drive from the cortex or thalamus and
asynchronous feedback inhibition from the globus pallidus acts to limit
or time action potential generation. In contrast, in idiopathic and
models of Parkinson's disease, the activity of subthalamic and
pallidal neurons becomes highly correlated and rhythmic bursting
activity emerges within the network (Bergman et al.
1994; Nini et al. 1995; Rodriguez et al.
1998). Under these conditions, synchronous GABAergic inputs from the globus pallidus may generate rebound firing in subthalamic neurons and oscillatory network behavior underlying tremor may emerge
in a manner similar to that described in the thalamus (McCormick and Bal 1997; Plenz and Kitai 1999).
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ACKNOWLEDGMENTS |
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This research was supported by Medical Research Council United Kingdom, National Institute of Neurological Disorders and Stroke Grant NS-24763, and European Community Grant BIOMED 2-BMH4-CT-97-2215.
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FOOTNOTES |
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Address for reprint requests: M. D. Bevan, MRC Anatomical Neuropharmacology Unit, Mansfield Road, University Department of Pharmacology, Oxford OX1 3TH, UK.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9 December 1999; accepted in final form 7 February 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) and divalent cations by the recorded neuron. In
contrast, the intracellular concentration of all ions and neutral
molecules is dominated by the pipette solution when the whole-cell
configuration is established. C: perforated recording of
a subthalamic neuron followed by a whole-cell recording. Because the
pipette solution contained a high [Cl
). EGABAA was measured
from these recordings as