Download Excitatory Postsynaptic Potentials Trigger a Plateau Potential in Rat

Excitatory Postsynaptic Potentials Trigger a Plateau Potential in Rat
Subthalamic Neurons at Hyperpolarized States
TAKESHI OTSUKA,1 FUJIO MURAKAMI,2,3 AND WEN-JIE SONG1
Department of Electronic Engineering, Graduate School of Engineering, Osaka University, Suita 565-0871;
2
Division of Biophysical Engineering, Graduate School of Engineering Science, Osaka University; and
3
Core Research for Evolutional Science and Technology/Murakami Laboratory, Center for Advanced
Research Projects, Osaka University, Toyonaka 560-8531, Japan
1
Received 5 March 2001; accepted in final form 26 June 2001
Otsuka, Takeshi, Fujio Murakami, and Wen-Jie Song. Excitatory
postsynaptic potentials trigger a plateau potential in rat subthalamic
neurons at hyperpolarized states. J Neurophysiol 86: 1816 –1825,
2001. The subthalamic nucleus (STN) directly innervates the output
structures of the basal ganglia, playing a key role in basal ganglia
function. It is therefore important to understand the regulatory mechanisms for the activity of STN neurons. In the present study, we aimed
to investigate how the intrinsic membrane properties of STN neurons
interact with their synaptic inputs, focusing on their generation and the
properties of the long-lasting, plateau potential. Whole cell recordings
were obtained from STN neurons in slices prepared from postnatal
day 14 (P14) to P20 rats. We found that activation of glutamate
receptor-mediated excitatory synaptic potentials (EPSPs) evoked a
plateau potential in a subpopulation of STN neurons (n ⫽ 13/22), in
a voltage-dependent manner. Plateau potentials could be induced only
when the cell was hyperpolarized to more negative than about ⫺75
mV. Plateau potentials, evoked with a depolarizing current pulse,
again only from a hyperpolarized state, were observed in about half of
STN neurons tested (n ⫽ 162/327). Only in neurons in which a
plateau potential could be evoked by current injection did EPSPs
evoke plateau potentials. L-type Ca2⫹ channels, Ca2⫹-dependent K⫹
channels, and TEA-sensitive K⫹ channels were found to be involved
in the generation of the potential. The stability of the plateau potential,
tested by the injection of a negative pulse current during the plateau
phase, was found to be robust at the early phase of the potential, but
decreased toward the end. As a result the early part of the plateau
potential was resistant to membrane potential perturbations and would
be able to support a train of action potentials. We conclude that
excitatory postsynaptic potentials, evoked in a subpopulation of STN
neurons at a hyperpolarized state, activate L-type Ca2⫹ and other
channels, leading to the generation of a plateau potential. Thus about
half of STN neurons can transform short-lasting synaptic excitation
into a long train of output spikes by voltage-dependent generation of
a plateau potential.
The subthalamic nucleus (STN) acts as a driving force of the
basal ganglia by exerting glutamatergic excitatory effect on the
output structures of the basal ganglia, the globus pallidus and
the substantia nigra (see Kitai and Kita 1987 for a review). The
significance of the STN in motor control has been implicated in
a clinical observation that pathological changes in the nucleus
causes hemiballism (Whittier 1947) and in animal experiments
in which manipulation of the activity of the nucleus dramatically affects motor behavior (Hamada and Hasegawa 1996;
Wichmann et al. 1994b). These observations indicate the importance of controlling outputs of the basal ganglia by STN
neurons. It is therefore crucial to know how the activity of STN
neurons is regulated for understanding basal ganglia function
in motor control.
The activity of a neuron is determined by extrinsic synaptic
inputs and intrinsic membrane properties. The STN is known
to receive excitatory input from the cortex (Fujimoto and Kita
1993; Hartmann-von Monakow et al. 1978; Kitai and Deniau
1981; Nambu et al. 1996) and the thalamus (Féger et al. 1994;
Mouroux and Féger 1993) and inhibitory inputs from the
globus pallidus (Groenewegen and Berendse 1990; Kita et al.
1983; Moriizumi and Hattori 1992). How STN neurons respond to these inputs depends on their membrane properties. In
slice studies, STN neurons fire regularly, increasing firing
frequencies linearly with the magnitude of injected currents
(Bevan and Wilson 1999; Nakanishi et al. 1987). This would
suggest that the STN works as a linear transformer relaying
excitatory inputs to its targets. Indeed, a recent study in anesthetized rat suggests that STN neurons follow the activity of
cortical neurons (Magill et al. 2000). STN neurons, however,
have intrinsic membrane properties, which can significantly
change neuronal firing pattern. The generation of a plateau
potential, a long-lasting depolarizing potential, for example,
has been described in a subset of STN neurons (Beurrier et al.
1999; Nakanishi et al. 1987; Otsuka et al. 1998, 1999; Overton
and Greenfield 1995; Song et al. 1998). Because of its slow
decay kinetics, the plateau potential would lead to a longlasting, high-frequency discharge in the absence of synaptic
inputs. In behaving animals, burst activity lasting several hundred milliseconds has been observed in STN neurons (Matsumura et al. 1992; Wichmann et al. 1994a). The generation of
a plateau potential may be one possible underlying mechanism
for such long-lasting burst.
Although the plateau potential can profoundly alter the output properties of STN neurons, no work has focused on how
the ability to generate plateau potentials affects synaptic inte-
Address for reprint requests: W.-J. Song, Dept. of Electronic Engineering,
Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita
565-0871, Japan (E-mail: [email protected]).
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.
INTRODUCTION
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0022-3077/01 $5.00 Copyright © 2001 The American Physiological Society
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PLATEAU POTENTIALS OF SUBTHALAMIC NEURONS
gration. Beurrier et al. (1999) reported a plateau potential in
STN neurons that in part supports recurrent membrane oscillations, leading to rhythmic burst firing of STN neurons. Others
have observed plateau potentials evoked by current injections
(Nakanishi et al. 1987; Overton and Greenfield 1995). But it is
not known whether plateau potentials can be triggered by
synaptic potentials. In the present study, we therefore tested
whether activation of excitatory synaptic inputs to STN neurons can trigger a plateau potential and if so, how the plateau
potential would interact with synaptic potentials. We found
that activation of glutamate receptor-mediated synaptic potentials triggered a plateau potential in about half of STN neurons,
only when the cells were hyperpolarized. Our results thus
suggest that about half of STN neurons transform excitatory
synaptic inputs into either a single spike or a train of spikes,
depending on membrane potential. Part of the results has been
published in abstract form (Otsuka et al. 1998, 1999; Song et
al. 1998).
METHODS
Slice preparation
Slice preparation including the STN was obtained from SpragueDawley rats (14 –20 postnatal days). All experiments were conducted
in compliance with the Guidelines for Use of Laboratory Animals of
Osaka University. Rats were anesthetized with ether and perfused
with a high-sucrose solution containing (in mM): 200 sucrose, 2.5
KCl, 0.5 CaCl2, 10 MgSO4, 1.25 KH2PO4, 26 NaHCO3, 10 glucose,
0.2 ascorbic acid, and 1 pyruvic acid (300 ⫾ 5 mOsm/l; pH, 7.4). The
brain was then removed, iced, and blocked for slicing. In the medium
described in the preceding text, 250- to 300-␮m (mostly 300 ␮m)thick horizontal slices were prepared using a Microslicer (Dosaka EM,
Japan). The slices were then incubated at room temperature (20°C) in
oxygenated Kreb’s solution containing (in mM): 126 NaCl, 2.5 KCl,
1.25 KH2PO4, 1 MgSO4, 2 CaCl2, 26 NaHCO3, and 10 glucose
(300 ⫾ 5 mOsm/l, pH, 7.4; bubbled with 95% O2-5% CO2). Ascorbic
acid (0.2) and 1 pyruvic acid (in mM) were added to the holding
solutions for improving tissue viability. After 1-h recovery period, a
slice was transferred to a recording chamber mounted on the stage of
an upright microscope (Olympus, Tokyo). The recording chamber
was continuously superfused with the oxygenated Kreb’s solution.
Recordings and data analyses
Whole cell recordings of STN neurons employed standard techniques (Edwards et al. 1989; Stuart et al. 1993). Electrodes were
pulled from glass capillary tubes (Narishige, Tokyo) and fire-polished.
In most experiments, the recording pipettes were filled with a solution
containing (in mM): 120 KCl, 3 MgCl2, 10 HEPES, 0.2 EGTA, 2
Na2ATP, 0.2 Li2GTP, 12 phosphocreatine, and 0.1 leupeptin (pH, 7.2;
270 ⫾ 5 mOsm/l) and had resistances of 5–7 M⍀ in the bath. The
liquid-junction potential was estimated to be 4.3 mV. All potentials
reported in this paper were corrected for this potential. In experiments
chelating internal Ca2⫹, the internal solution consisted of (in mM) 100
KCl, 3 MgCl2, 10 HEPES, 20 BAPTA, 2 Na2ATP, 0.2 Li2GTP, 12
phosphocreatine, 0.1 leupeptin (pH, 7.2; 270 ⫾ 5 mOsm/l), and the
concentration of KCl of the external solution was changed to 1.5 mM
to adjust K⫹ equilibrium potential. We also recorded with a low-Cl⫺
internal solution containing (in mM) 70 K2SO4, 2.5 MgCl2, 1.0
EGTA, 0.1 CaCl2, 35 HEPES, 30 N-methyl-D-glucamine (NMG), 2
Na2ATP, 0.2 Li2GTP, and 0.1 leupeptin (pH 7.2, 270 ⫾ 5 mOsm/l).
Recordings were obtained with an EPC-7 amplifier (List-MedicalElectronics, Darmstadt, Germany) controlled with a Pentium PC
running pCLAMP (version 6.0) or Axoscope (Axon Instruments,
J Neurophysiol • VOL
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Foster City, CA). Synaptic responses were evoked by electrical stimulation applied through a bipolar tungsten electrode using a Master-8
stimulator (AMPI, Jerusalem, Israel). The electrode was placed in a
region rostral to the STN. A single current pulse of 0.1– 0.5 mA in
amplitude and 100 ␮s in duration was used for stimulation. Data
analyses were performed with AxoGraph (Axon Instruments) and
Kaleidagraph (Albeck Software, Reading, PA). Data are represented
as means ⫾ standard deviation (SD) and statistical difference between
samples was tested using Mann-Whitney U test, unless mentioned
otherwise. Significance was accepted when P ⬍ 0.05.
Drugs
All reagents were obtained from Sigma Chemical (St. Louis, MO)
except nifedipine and 6,7-dinitroquinoxaline-2,3-dione (DNQX),
which were obtained from RBI (Natick, MA). Biocytin was diluted in
the internal solution at the concentration of 5 mg/ml. Other drugs were
diluted in oxygenated Kreb’s solution and applied to the slice. Nifedipine was made up as concentrated stocks in 95% ethanol and diluted
immediately before use. DNQX was dissolved in dimethylsulfoxide.
When using these drugs, equal concentrations of the solvent were
added to all control solutions. For the tetraethylammonium chloride
(TEA) experiment, the Kreb’s solution was modified by replacing
NaCl (50 mM) with NMG (50 mM) and was used as the control
solution; TEA solutions were prepared by replacing NMG with an
equimolar concentration of TEA. Solutions containing bicuculline or
nifedipine were protected from ambient light.
Histology
To verify that recorded cells were in fact STN neurons, biocytin
was always included in the internal solution (Horikawa and Armstrong 1988). The avidin-biotin-horseradish peroxidase reaction was
used to visualize recorded neurons. After recording, slices were fixed
with a solution containing 4% paraformaldehyde in phosphate buffer
(0.1 M; pH, 7.4). After rinsing in Tris-buffered saline (TBS; 50 mM;
pH, 7.4), the slices were treated with a mixture of 10% methanol and
0.3% H2O2 for 20 –30 min, rinsed again in TBS, and treated with TBS
containing 0.5% Triton x-100. After washes with TBS, the slices were
incubated for 2 h in the avidin-biotin-horseradish peroxidase complex
(1%; Vector Laboratories, Burlingame, CA) at room temperature,
washed in TBS, and reacted with a mixture of 3,3⬘-diaminobenzidine
tetrahydrochloride (0.05%) and H2O2 (0.003%) in TBS for 5–10 min.
The slices were then rinsed several times in TBS and mounted on
gelatin-coated glass slides. The mounted slices were stained with
methylene blue for identification of the nucleus, dehydrated in graded
ethanol series, cleared in xylene, and coverslipped with Entellan New
(Merck, Darmstadt, Germany) for observation with a light microscope.
RESULTS
Recordings were obtained from 327 neurons. Each recorded
neuron was labeled intracellularly with biocytin, and all were
found within the STN (Fig. 1A). The stained STN neurons had
soma diameters of 15–30 ␮m and two to six primary dendrites.
The resting membrane potential was ⫺62.65 ⫾ 5.10 mV and
the input resistance at rest, estimated with a negative current
pulse (⫺10 pA), was 0.66 ⫾ 0.22 G⍀.
Induction of plateau potentials by synaptic potentials
To examine the response of STN neurons to excitatory
synaptic inputs, recordings were obtained while stimulation at
a location rostral to the STN was performed to evoke synaptic
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T. OTSUKA, F. MURAKAMI, AND W.-J. SONG
FIG. 1. Responses to synaptic stimulation in
subthalamic nucleus (STN) neurons. A: a photomicrograph of a 300-␮m-thick slice stained with
methylene blue. Arrowhead indicates the recorded
cell labeled intracellularly with biocytin. Scale
bar ⫽ 50 ␮m. B: a synaptic potential evoked by
stimulation of a site rostral to the STN. Coapplication of 6,7-dinitroquinoxaline-2,3-dione (DNQX)
and 2-amino-5-phosphonovalerate (APV) abolished
the potential. C: in the same cell, increasing the
stimulus strength evoked a single action potential
at the resting membrane potential. D: at a hyperpolarized membrane potential, however, stimulation with the same strength as in C evoked a
long-lasting potential and a short train of spikes.
Membrane potentials were hyperpolarized by injection of a constant current.
potentials. Bicuculline (50 ␮M) was included in the external
solution to block inhibitory synaptic potentials. In response to
stimulation, depolarizing potentials or inward currents were
observed in most of the neurons examined (n ⫽ 32/41). Stimulation at sites rostrolateral to the STN failed to evoke a
response (n ⫽ 7). Coapplication of DNQX (10 ␮M), a non-Nmethyl-D-aspartate (non-NMDA) receptor blocker, and 2-amino-5-phosphonovalerate (APV; 50 ␮M), an NMDA receptor
blocker, abolished the potentials (n ⫽ 4, Fig. 1B), indicating
that these potentials are excitatory postsynaptic potentials
(EPSPs) mediated by glutamate receptors. Application of either DNQX or APV alone revealed that 54 –71% of the EPSP
amplitude was mediated by non-NMDA receptors at ⫺80 mV
(n ⫽ 3). At 20°C, the latency of the EPSPs was 4.4 –7.2 ms and
changed ⬍0.5 ms with varying stimulus strength. Assuming a
Q10 value of 3.5 (Hirano et al. 1986), the latencies correspond
to latencies of 0.5– 0.9 ms and the latency change corresponds
to a value ⬍0.1 ms, at 37°C, suggesting that the EPSPs are of
monosynaptic nature.
With increased stimulus strength, the EPSPs always triggered a single action potential in STN neurons at resting
membrane potentials (n ⫽ 22; Fig. 1C). When the membrane
potential was hyperpolarized to about ⫺75 mV, however,
stimulation with the same strength evoked a long-lasting potential, or a plateau potential, in a subpopulation of STN
neurons (n ⫽ 13 of 22, Fig. 1D). The holding current required
to hyperpolarize the membrane potential to ⫺75 to ⫺85 mV
ranged from ⫺10 to ⫺30 pA. On the rising phase of the plateau
potential, a short train of action potentials (1–5 spikes) was
evoked (Fig. 1D). When the stimulus intensity was decreased,
only EPSPs were observed. Gradually changing the stimulus
strength revealed that the amplitude of the EPSPs right before
the occurrence of plateau potentials ranged from ⫺61 to ⫺67
mV (n ⫽ 5). Neurons in which plateau potentials were not
observed always discharged a single action potential at the
peak of the EPSPs either at rest or at hyperpolarized states, for
stimulus intensities up to 0.5 mA (n ⫽ 9). These results suggest
that EPSPs are capable of triggering a plateau potential in a
subpopulation of STN neurons, in a voltage-dependent manner.
J Neurophysiol • VOL
Induction of plateau potentials by injected current pulses
To examine how plateau potentials affect synaptic integration in STN neurons, we next studied the properties of plateau
potentials in STN neurons. For this purpose, plateau potentials
were evoked with current injection instead of synaptic activation for the ease of experimentation.
At resting membrane potentials, injection of depolarizing
current pulses evoked action potentials either during the initial
phase of the current (70%, n ⫽ 205/294; Fig. 2A, top) or during
the entire period of current injection (n ⫽ 89; Fig. 2C, top).
The membrane potential returned to rest in an exponential
manner after termination of the current pulse (Fig. 2, A and C,
top).
At hyperpolarized potentials, however, a long-lasting potential was induced that far outlasted current injection (Fig. 2C,
bottom), again in a subpopulation of STN neurons. Other cells
exhibited an exponential relaxation of membrane potential
after termination of current injection (Fig. 2A, bottom). For a
quantitative description of the membrane potentials after current termination, we measured the half-decay time defined as
the time interval from the pulse end to the time when the
potential had decayed to half-amplitude at the current pulse
end. STN neurons could easily be divided into a population
having short half-decay times (30 ⫾ 0.13 ms, n ⫽ 146) and a
population having much longer half-decay times (0.66 ⫾
0.49 s, range 0.20 –3.0 s; n ⫽ 148). We defined a potential with
a half-decay time ⱖ0.2 s as a plateau potential. About half of
STN neurons tested (n ⫽ 148/294) generated a plateau potential at hyperpolarized state.
Plateau potentials were also observed with an internal solution of low Cl⫺ concentration (see METHODS) at 30°C, again in
a subset of neurons (n ⫽ 14/33). Under this recording condition, some STN neurons showed spontaneous activity at resting
membrane potentials (2–10 Hz, n ⫽ 9/33), although these
activities disappeared with membrane hyperpolarization; all
STN neurons discharged during the entire period of current
injection. Plateau-generating neurons fired 5.1 ⫾ 1.6 (n ⫽ 14)
spikes during current injection (100 ms in duration, 50 pA in
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PLATEAU POTENTIALS OF SUBTHALAMIC NEURONS
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FIG. 2. Induction of plateau potentials with current pulses.
A: recordings from a nonplateau-generating cell. Top: injection
of a depolarizing pulse current (50 pA), shown as the bottom
trace, at the resting membrane potential, depolarized the membrane potential and evoked action potentials. The membrane
potential returned to the resting level immediately after the
termination of the current in an exponential manner. Middle:
injection of the same current at a hyperpolarized state evoked a
similar response, though an increase of membrane resistance is
obvious. B: a recording from the same neurons as in A. A
rebound action potential was evoked on termination of a hyperpolarizing current (⫺50 pA). During injection of the current, the
membrane potential exhibited a tendency to return to the resting
level, indicating the presence of an H current in this neuron. C:
recordings from a plateau-generating neuron. Top: injection of
a depolarizing pulse current (50 pA, bottom), at the resting
membrane potential, depolarized the membrane potential and
evoked action potentials. The membrane potential relaxed to the
resting level immediately after the termination of the current, as
in A. Middle: injection of the same current at a hyperpolarized
state, however, evoked a plateau potential that outlasted current
injection. D: a recording from the same neuron as in C. A
plateau potential was induced as a rebound potential on termination of a negative current (⫺50 pA).
amplitude), which is not significantly different from that of
nonplateau-generating neurons (4.5 ⫾ 2.1, n ⫽ 19; P ⬎ 0.05).
A plateau potential was also generated after termination of a
hyperpolarizing current pulse (n ⫽ 19; Fig. 2D). Such a potential was observed only in neurons in which a plateau potential could be evoked by a depolarizing current pulse, at
hyperpolarized states (compare Fig. 2, B–D).
We next tested to what membrane potentials the cell has to
be hyperpolarized for a depolarizing pulse to evoke a plateau
potential. Membrane potentials were gradually hyperpolarized
by changing the amount of injected constant current, while a
depolarizing current pulse (50 ms) was injected to test if a
plateau potential could be induced. As a result, a plateau
potential was induced in an all-or-none manner, across certain
membrane potentials (Fig. 3A). The membrane potential at
which a plateau potential was first induced was referred to as
threshold potential. Shown in Fig. 3B is a histogram of the
threshold potentials from 19 neurons. The threshold potential
was ⫺74.98 ⫾ 1.96 mV.
From a hyperpolarized state, the membrane potential had to
be depolarized to a certain potential for plateau potential to
occur. This depolarizing threshold for the plateau potential was
difficult to determine from the rising phase of the potential, but
with gradual change of injected current, the potentials immediately before the occurrence of plateau potentials ranged from
⫺62 to ⫺67 mV, corresponding to an injected current of ⬃10
pA. The amplitude of the plateau potential was independent of
the suprathreshold current amplitude, ranging from 10 to 100
pA.
To estimate the distribution of plateau-generating neurons in
the STN, we divided the nucleus into three equal parts by
length, either along the rostrocaudal or lateromedial axis.
Along the rostrocaudal axis, the ratio of plateau-generating
neurons to nonplateau-generating neurons was 46.9% (n ⫽
FIG. 3. The threshold hyperpolarization level for the plateau
potentials to be induced. A: the cell was held at different
membrane potentials by injecting constant currents, while a
short depolarizing pulse was applied to test if plateau potential
can be induced. The plateau potential was induced only when
the membrane potential was kept at ⫺74 mV or more negative.
We call ⫺74 mV the threshold potential for this case. B: the
histogram of threshold potentials determined in 19 STN neurons. The distribution of threshold potentials had a peak at
about ⫺74 mV.
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T. OTSUKA, F. MURAKAMI, AND W.-J. SONG
15/32) in the rostral part, 47.6% (n ⫽ 32/68) in the middle part,
and 51.2% (n ⫽ 15/32) in the caudal part. Along the lateromedial axis, however, the ratio in the lateral, middle, and
medial part of the STN was 60.3% (n ⫽ 38/63), 44.9% (n ⫽
22/49), and 29.0% (n ⫽ 9/31), respectively. Thus plateaugenerating neurons tend to be located in the lateral part of the
nucleus. Although the morphology of plateau-generating neurons did not appear to differ from that of nonplateau-generating
neurons, the input resistance at resting membrane potentials of
plateau-generating neurons was found to be significantly larger
than that of nonplateau-generating neurons (0.813 ⫾ 0.07 vs.
0.524 ⫾ 0.05 G⍀, n ⫽ 148; Student’s t-test, P ⬍ 0.005).
To test whether plateau potentials evoked by synaptic potentials and those evoked by current injection are of the same
nature, we tried to evoke plateau potentials in the same neuron
both by synaptic activation and by current injection. In such
experiments, EPSPs evoked plateau potentials only in neurons
in which a plateau potential could be evoked by injection of
current pulses at hyperpolarized states (n ⫽ 13), suggesting
that plateau potentials evoked by EPSPs and those evoked by
current injections are attributable to a common membrane
mechanism.
Effect of temperature
It was puzzling that action potentials were not evoked during
the plateau phase of the plateau potential. We suspected that
this might be because the experiment was carried out at room
temperature. To verify this hypothesis, we raised the temperature from 20 to 25°C. As shown in Fig. 4, although a plateau
potential did not evoke action potentials at 20°C (Fig. 4A), it
evoked action potentials even at its late phase at 25°C (Fig. 4B;
n ⫽ 6). Raising the temperature also appeared to increase the
duration of the plateau potential (compare Fig. 4, A to B).
Stability of plateau
To study how the plateau potentials interact with synaptic
inputs, we tested the stability of the plateau potentials. Because
plateau potentials were not terminated by action potentials
(Fig. 4B), they appear to be resistant to perturbations of depolarizing potentials. To test the effect of inhibitory synaptic
potentials, a negative current pulse, used to represent an inhibitory synaptic current, was injected at successive timings during the course of the plateau potential induced with a short
pulse (50 ms; Fig. 5). The negative current had an amplitude of
⫺60, ⫺80, or ⫺90 pA. The duration of the current was
determined in reference to inhibitory synaptic currents in STN
neurons (Shen and Johnson 2000), and a 20-ms duration was
used. The stability of the plateau potential was evaluated by the
ratio of the peak potential after the current pulse to the potential
immediately before the current, referred to as stability index
here; a stable potential would give rise to a stability index of
one. Shown in Fig. 5B is the stability index estimated at
successive time intervals during the course of plateau potentials. The stability index was close to one during the early
phase of the potential and then fell gradually afterwards. During the initial 10% of the plateau, however, the stability index
was always ⬎1 (1.18 ⫾ 0.06; n ⫽ 4). Toward the end of the
potential, the stability index fell abruptly. To compare the
effect of the amplitude of the negative current, data between 30
and 70% of the plateau duration was fitted with an exponential
function in the form
Stability index ⫽ 1⫺ exp共共T ⫺ A兲ⲐB兲
where T is percent plateau duration, B is time constant, and A
represents delay (Fig. 5B, inset). The stability index decreased
to 0.7 in 69 ⫾ 8% of plateau duration when the current
amplitude was ⫺60 pA. This percentage was 62 ⫾ 8% for a
current of ⫺80 pA and 49 ⫾ 8% for a current of ⫺90 pA. Thus
the early part of the plateau potential was resistant to inhibitory
perturbations and would be able to support a train of spikes,
although the plateau potential may be terminated by inhibitory
synaptic inputs toward the end of the potential.
Subcellular origin for the generation of plateau potentials
FIG. 4. Temperature dependence of the firing properties of a plateaugenerating neuron. A: a recording at 20°C. No action potential was observed
during the plateau phase of the plateau potential. B: a recording from the same
neuron as in A at 25°C. Action potentials were evoked during the plateau
phase. The injected current was 50 pA for both A and B.
J Neurophysiol • VOL
Whether plateau potentials in STN neurons are generated in
the soma or in the dendrites is of obvious significance for
synaptic integration. To address this question, we tested the
effect of voltage-clamping somatic membrane on the ability of
EPSPs in evoking plateau potentials (currents). Anatomical
evidence suggests that excitatory synaptic inputs end on distal
dendrites of STN neurons (Bevan et al. 1995). Thus EPSPs in
STN neuron, as those shown in Fig. 1, are expected to be
induced from distal dendrites. If a plateau potential occurs at
the soma, voltage-clamping the soma would prevent the induction of the plateau by EPSPs; in contrast, considering the
filtering effect of dendrites, a plateau potential occurring at
distal dendrites may not be blocked by voltage-clamping the
soma and would thus give rise to a plateau current at the soma.
To verify that excitatory synaptic inputs occur at sites electrotonically distant from the soma, we tried to determine the
reversal potential of the EPSPs, which is calculated to be ⫹6.4
mV for an appropriate voltage control, assuming equal permeability of Na⫹ and K⫹ and a Ca2⫹ permeability of 1.17 relative
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PLATEAU POTENTIALS OF SUBTHALAMIC NEURONS
FIG. 5. The stability of the plateau potential tested with hyperpolarizing
currents. A: plateau potentials were evoked from a hyperpolarized state with a
current pulse (100 pA, 50 ms). A negative pulse current (⫺60 pA, 20 ms) was
injected at successive time intervals after the initiation of the potential. B: the
ratio of the peak value of the potential after the negative current pulse to the
potential immediately before the current injection, for three current amplitudes
(⫺60, ⫺80, and ⫺90 pA), was plotted against plateau potential duration
normalized to one. The ratio is close to one during the early phase of the
plateau potential. Toward the end of the potential, the ratio fell abruptly. Inset:
data between 30 and 70% of the plateau duration was fitted with exponential
curves. With increasing current amplitude, the potential was of shorter duration.
to Na⫹; intracellular Ca2⫹ concentration was assumed to be
100 nM (Götz et al. 1997; Mayer and Westbrook 1987). EPSPs
were evoked in the same way as described in the preceding
text. As a result, the reversal potential was ⫹21.0 ⫾ 10.8 mV
(n ⫽ 4). In three other tested cells, the EPSPs did not reverse
1821
for potentials up to ⫹20 mV. These results suggest that excitatory synaptic inputs to STN neurons are electrotonically
distant from the soma and are consistent with previous anatomical observations (Bevan et al. 1995).
To test the effect of voltage-clamping somatic membrane on
the ability of EPSPs in evoking plateau potentials, a plateau
potential was first elicited in current-clamp mode by EPSPs
(Fig. 6A). In voltage-clamp mode, however, only a transient
inward current was evoked in the same neuron, in response to
the same stimulation (Fig. 6B). To study the nature of the
current, we compared its time course to that of currents recorded in the same way from nonplateau-generating neurons.
Shown in Fig. 6, C and D, is an example of recordings from a
nonplateau-generating neuron. In both plateau- and nonplateau-generating cells, the current recorded in voltage-clamp
mode decayed in an exponential manner. The time constant
was 12.0 ⫾ 2.0 ms (n ⫽ 7) in plateau-generating neurons and
14.5 ⫾ 3.9 ms (n ⫽ 6) in nonplateau-generating neurons,
which is not significantly different from that of plateau-generating cells (P ⬎ 0.05). This result suggests that the current
recorded in plateau generating cells was not related to the
plateau potential but was likely a pure synaptic current. In
plateau-generating cells, doubling the stimulus intensity increased the amplitude of the current, but did not change its
kinetics (decay time constant, 12.7 ⫾ 2.2 ms, n ⫽ 7; P ⬎ 0.05).
Taken together, these results suggest the possibility that plateau potentials in STN neurons occur at a region where membrane potential is controlled by an electrode in the soma. This
region is likely to be the soma and/or proximal dendrites.
Ionic mechanisms of a plateau potential
The observation that plateau potentials can be induced only
at hyperpolarized membrane potentials suggests that voltagedependent conductances are involved in the generation of the
plateau potentials. Because a plateau potential could be induced only from a hyperpolarized state, it is natural to consider
channels deinactivated at hyperpolarized potentials to be involved in the generation of plateau potentials. An obvious
FIG. 6. Subcellular origin of the plateau
potential. A: in current-clamp mode, stimulation of a site rostral to STN evoked a
plateau potential. Subthreshold membrane
oscillations (arrowhead) during the plateau
phase was observed in this and 33 other STN
neurons. The oscillating frequency was
19.9 ⫾ 7.7 Hz. Application of TTX (1 ␮M)
abolished the membrane oscillation (n ⫽ 5).
Inset: autocorrelation function of the potential indicated by the arrowhead. B: in voltage-clamp mode, stimulation at the same
strength as in A evoked a transient current.
Voltage was clamped to ⫺80 mV. C: current-clamp recording from a nonplateaugenerating cell. Only a synaptic potential
was evoked on top of which an action potential was triggered. D: a voltage-clamp
recording from the same neuron with the
same stimulus strength as in C. Holding potential was ⫺80 mV. Shaded curves in B and
D are exponential fit to the current.
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T. OTSUKA, F. MURAKAMI, AND W.-J. SONG
candidate is the low-threshold Ca2⫹ channel (or T channel).
The existence of T channels in STN neurons has been documented before (Beurrier et al. 1999; Nakanishi et al. 1987;
Song et al. 2000), and its possible involvement in the generation of plateau potentials in STN neurons has been suggested
(Beurrier et al. 1999). Because of the transient nature of the T
channels (Carbone and Lux 1984), it is unlikely that a plateau
potential is maintained by T channels. To search for conductances involved in the maintenance of plateau potentials, we
tested the effect of blocking channels that inactivate or deactivate slowly. Previous studies have suggested that Ca2⫹ (Nakanishi et al. 1987) and L-type Ca2⫹ channels (Beurrier et al.
1999) are required for the generation of plateau potentials in
STN neurons. These suggestions were confirmed in our study:
the generation of a plateau potential was blocked by removing
Ca2⫹ from the external solution (n ⫽ 3; data not shown), and
nifedipine (10 ␮M), an L-type channel blocker, strongly reduced the duration of plateau potentials (Fig. 7A; n ⫽ 5),
shortening the half decay time from 0.808 ⫾ 0.185 s in control
condition to 0.135 ⫾ 0.026 s (P ⬍ 0.05).
It is conceivable that the current through L-type channels is
involved in the maintenance of the plateau potential, but it is
also possible that it is the increase in intracellular Ca2⫹ concentration that is important for the maintenance of plateau
potentials because intracellular Ca2⫹ activates a number of ion
channels of slow kinetics. Actually, a Ca2⫹-dependent cation
conductance has been suggested to be involved in the plateau
potential (Beurrier et al. 1999). We examined the effect of
intracellular Ca2⫹ by including a high concentration (20 mM)
of the Ca2⫹ chelating reagent bis-(o-aminophenoxy)N,N,N⬘,N⬘-tetraacetic acid (BAPTA) in the internal recording
solution. Immediately after going from the cell-attached to the
whole cell configuration, plateau potentials elicited with a
depolarizing pulse had half decay times of 0.34 ⫾ 0.01 s (Fig.
7B, top). Over time, the duration of plateau potentials gradually
increased, reaching a stable value at ⬃10 min of whole cell
recording (Fig. 7B, bottom; n ⫽ 5). The half decay time at 10
min of whole cell recording was 0.65 ⫾ 0.01 s, which is
significantly longer than the value on establishment of the
whole cell configuration (P ⬍ 0.05). In addition to the elongation of the duration of the plateau potential, a reduction in
plateau amplitude was also noticed (Fig. 7B). These results
suggest that a Ca2⫹-dependent outward current and possibly
inward currents are involved in the maintenance of the plateau
potential.
To search for conductances involved in the repolarization of
plateau potentials, we tested the effect of TEA. As shown in
Fig. 7C (top), a plateau potential was induced in the presence
of TTX (1 ␮M), a result in agreement with a previous finding
(Beurrier et al. 1999); addition of TEA (10 mM) to the bath
solution increased the duration of the plateau potential (Fig.
7C, bottom). The half decay time was significantly increased
by TEA from 0.49 ⫾ 0.05 to 0.79 ⫾ 0.08 s (P ⬍ 0.05, n ⫽ 5).
Taken together with the effects of intracellular Ca2⫹ chelation,
these results suggest that the repolarization of plateau potentials is mediated by both Ca2⫹-dependent K⫹ channels and
TEA-sensitive K⫹ channels.
DISCUSSION
In the present study, we investigated how intrinsic membrane properties of STN neurons may interact with synaptic
inputs. We have found that activation of excitatory synaptic
inputs evoked a plateau potential, in a voltage-dependent manner. Plateau potentials, evoked with a depolarizing pulse, were
observed in about half of STN neurons. L-type Ca2⫹ channels,
Ca2⫹-dependent K⫹ channels, and TEA-sensitive K⫹ channels
were found to be involved in the generation of the potential.
We conclude that EPSPs, evoked at a hyperpolarized state,
activate L-type Ca2⫹ channels and other channels, leading to
the generation of a plateau potential. Thus about half of STN
neurons can transform short-lasting synaptic excitation into a
long train of output spikes, in a voltage-dependent manner.
FIG. 7. Ionic mechanisms of the plateau potential. A: current pulse (50pA; bottom)-evoked plateau potentials (top) were
suppressed by application of nifedipine (10 ␮M; middle). B: chelation of intracellular Ca2⫹ with bis-(o-aminophenoxy)-N,N,N⬘,N⬘tetraacetic acid (BAPTA) increased the duration of a plateau potential. Top: a plateau potential evoked with a current pulse (bottom)
immediately after establishment of the whole cell recording configuration. The pipette solution contained 20 mM BAPTA. Middle:
the recording 10 min after establishment of the whole cell recording configuration in the same neuron. C: plateau potentials were
observed in the presence of TTX (1 ␮M). Application of TEA (50 mM) greatly enhanced the duration of the plateau potential.
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PLATEAU POTENTIALS OF SUBTHALAMIC NEURONS
Ionic mechanisms
Although the occurrence of a plateau potential in STN
neurons has been reported before (Beurrier et al. 1999; Nakanishi et al. 1987; Overton and Greenfield 1995), we have
shown for the first time that a plateau potential in STN neurons
can be induced by activation of synaptic inputs from hyperpolarized membrane potentials. The EPSPs recorded here were
evoked by stimulation of a site rostral to the STN. Because
axon collaterals of fibers descending in the cerebral peduncle
enter the STN from the rostral aspect (Iwahori 1978), the
EPSPs are possibly of cortical origin, although we cannot
exclude the contribution of parafascicular thalamic origin. Previous in vivo studies have found that STN neurons exhibit
prolonged depolarizations in response to stimulation of the
cortex (Fujimoto and Kita 1993; Kitai and Deniau 1981).
These depolarizations, however, appear different from plateau
potentials in nature, because the duration of the depolarizations
is only ⬃20 ms.
We have reported in abstract form that plateau potentials in
STN neurons can be evoked only when the membrane potential
is hyperpolarized (Otsuka et al. 1998, 1999; Song et al. 1998).
Similar results were reported by Beurrier et al. (1999), although there was a quantitative difference: in Beurrier et al.
(1999) plateau potentials were observed in a voltage range
from ⫺50 to ⫺70 mV, while in the present study, STN neurons
had to be hyperpolarized to about ⫺75 mV for the plateau
potential to occur. Why then does the membrane potential have
to be hyperpolarized for plateau potentials to occur? One
possibility is that hyperpolarization deinactivates voltage-dependent channels that are involved in the generation of plateau
potentials. T-type Ca2⫹ channels, which are present in STN
neurons (Beurrier et al. 1999, 2000; Nakanishi et al. 1987;
Song et al. 2000), are well known to be inactivated at resting
membrane potentials and deinactivated at hyperpolarized potentials (Carbone and Lux 1984; Mouginot et al. 1997). However, because of the transient nature of T-type current, it is
expected that T-type channels may play a role in the induction,
but not the maintenance, of plateau potential. What channels
are then activated to produce a plateau potential? In principle,
the occurrence of a plateau potential requires the steady-state
current-voltage (I-V) curve to cross zero current with a negative slope. Thus in STN neurons, synaptic potentials have to
activate an inward current that decays only slowly for plateau
potentials to occur. The channel giving rise to this current has
to be again inactivated (or partially inactivated) at the resting
membrane potential and deinactivated at hyperpolarized potentials. Possible candidates for such channels include highthreshold Ca2⫹ channels and probably noninactivating Na⫹
channels. Ca2⫹-dependent cation channels may also be involved if Ca2⫹ channels are activated. Although a persistent,
TTX-sensitive Na⫹ channel has been reported in STN neurons
(Beurrier et al. 2000; Bevan and Wilson 1999), it does not
appear to be essential for plateau potentials to occur because
plateau potentials in STN neurons could be evoked in the
presence of TTX (see Fig. 7) (Beurrier et al. 1999). Plateau
potentials have also been found and well studied in motoneurons and interneurons of the spinal cord (reviewed in Kiehn
1991). In the spinal cord, L-type Ca2⫹ channels can impart a
negative slope region to the steady-state I-V curve (Hounsgaard
and Kiehn 1989; Svirskis and Hounsgaard 1997). Nakanishi et
J Neurophysiol • VOL
1823
al. first showed that plateau potentials in STN neurons were
Ca2⫹ dependent (Nakanishi et al. 1987). After that, Beurrier et
al. identified the Ca2⫹ channel to be of the L type (Beurrier et
al. 1999), and this was confirmed in the present study. In a
computer simulation study, we found that the voltage dependence of plateau potential induction can be solely attributed to
voltage-dependent inactivation of L-type Ca2⫹ channel (Otsuka et al. 2000). We, therefore propose that the voltage
dependence of L-type channels plays an important role in the
voltage-dependent induction of plateau potentials in STN neurons.
Besides carrying an inward current, Ca2⫹ influx may also
cause activation of Ca2⫹-dependent inward currents. Actually,
Beurrier et al. have found that chelating intracellular Ca2⫹
greatly shortened the duration of STN plateau potentials and
concluded that a Ca2⫹-dependent cation channel is activated
and is essential for the maintenance of plateau potentials (Beurrier et al. 1999). Chelating intracellular Ca2⫹, however, enhanced the duration of plateaus in the present study (see Fig.
7). Because a Ca2⫹-dependent K⫹ current is obvious in STN
neurons (e.g., Fig. 1), enhancement of plateau duration by
chelating intracellular Ca2⫹ is expected. The reduction in plateau amplitude by intracellular BAPTA observed in the present
study, however, might be attributable to the blocking of Ca2⫹dependent cation channels.
Subcellular origin of the plateau potential
Although plateau potentials have been reported in STN
neurons for a long time, it is not known whether the potential
is generated in the dendrites or soma. If dendrites are the origin
of plateau potentials, then plateau potentials of different durations may be generated in several dendrites of the same neuron.
The integrated potential at the soma could thus be a step-wise
potential (but this may not occur in slice preparation, where
dendrites are not all preserved) (Reuveni et al. 1993) and
would produce complex spiking behavior. In contrast, if the
soma is the origin, STN neurons would show simpler discharge
patterns. Thus the site of origin of plateau potentials has
significance in synaptic integration and in regulating firing
behavior.
Our strategy for addressing this issue took advantage of the
fact that excitatory synaptic inputs to STN neurons end on
distal dendrites. Thus if a plateau potential occurs in dendrites,
voltage-clamping the soma would still allow the plateau potential to be evoked in dendrites by the synaptic input. In this
case, an inward current similar in shape to the plateau is
expected to be recorded at the soma. Because such currents
were never observed, plateau potentials in STN neurons appear
to be generated in the soma. This inference is consistent with
previous findings that L-type Ca2⫹ channels, which are essential for plateau potentials, tend to be localized in the soma (Hell
et al. 1993). Nevertheless other possibilities cannot be excluded at this time because our current argument is based on
negative findings.
Functional significance
The STN receives excitatory inputs from the cortex (Fujimoto and Kita 1993; Hartmann-von Monakow et al. 1978;
Kitai and Deniau 1981; Nambu et al. 1996). Because of the
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T. OTSUKA, F. MURAKAMI, AND W.-J. SONG
voltage dependence of the generation of plateau potential,
cortical input to the STN will be transformed into either a
single or a train of action potentials, depending on the membrane potential of STN neurons at the time of the input. What
may hyperpolarize the cell for a plateau potential to occur?
Opening of K⫹ channels by metabolic signaling pathways is
one possibility. High-frequency inhibitory input from, for example, the globus pallidus, would also help hyperpolarize the
cell. It is an important task to identify the pathway that hyperpolarizes STN neurons in future studies.
Because a plateau potential is more or less a long-lasting,
stereotyped potential, generation of a plateau potential would
lead to a reduction in spatiotemporal integrative ability of the
cell. The benefit of using a plateau potential, in addition to
transforming a single input volley into a train of output spikes,
may lie in the generation of rhythmic bursting in STN-related
neuronal networks. A previous study has shown that STN
neurons “switch from single-spike activity to burst-firing
mode” and suggested plateau potentials are involved in the
generation of rhythmic burst activity (Beurrier et al. 1999). In
our experiments, rhythmic burst activity was seldom observed.
This is consistent with the recent observation in explant culture
that STN neurons exhibit pacemaker activity when STN is in
the STN-GP network but not when STN is alone (Plenz and
Kitai 1999). Our observation that plateau potentials were observed in about half of STN neurons is in coincidence with the
observation by Plenz and Kitai that about half of STN neurons
exhibits pacemaker activity (Plenz and Kitai 1999). This coincidence suggests the possibility that plateau potentials in STN
neurons are involved in the generation of oscillatory bursting in
the STN-GP network. Two features of STN plateau potentials
may be relevant. First, because a plateau potential can be
evoked as a rebound potential (see Fig. 2) (Beurrier et al. 1999;
Overton and Greenfield 1995), a short train of spikes in GP
neurons would hyperpolarize STN neurons and a plateau potential would then occur as a rebound potential, evoking a train
of spikes in STN neurons. Second, STN activity would cause
immediate feedback inhibition from the GP, but this inhibition
might not immediately terminate STN spiking activity because
the early part of plateau potentials appears to be resistant to
inhibitory perturbations.
We thank S. Maeda for technical assistance in data analysis.
This work was supported by the Uehara Foundation, Grants-in-Aid for
Scientific Research on Priority Areas (Grants 12210099, 12053247, and
11170232) from the Ministry of Education, Science, and Culture, Japan to
W.-J. Song, and a grant from Core Research for Evolutional Science and
Technology, Japan Science and Technology Corporation to F. Murakami.
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