Download Conductance-Based Model of the Voltage

J Neurophysiol 92: 255–264, 2004;
10.1152/jn.00508.2003.
Conductance-Based Model of the Voltage-Dependent Generation of a Plateau
Potential in Subthalamic Neurons
Takeshi Otsuka, Takafumi Abe, Takahisa Tsukagawa, and Wen-Jie Song
Department of Electronic Engineering, Graduate School of Engineering, Osaka University, Suita 565-0871, Japan
Submitted 27 May 2003; accepted in final form 23 February 2004
The subthalamic nucleus (STN) is an oval-shaped small
nucleus, consisting only of glutamatergic projection neurons,
in the basal ganglia. It projects to the output structures of the
basal ganglia, the globus pallidus (GP), and the substantia nigra
(Kita and Kitai 1987; Kita et al. 1983b; Kitai and Kita 1987;
Van der Kooy and Hattori 1980). Despite its small size, the
STN plays important roles in motor control. Pathological
changes in the nucleus cause hemiballism (Whittier 1947),
suggesting that the STN plays a pivotal role in voluntary
movement control (Mink and Thach 1993; Wichmann and
DeLong 1996). Furthermore, manipulation of the activities of
STN neurons strongly 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. Therefore it is crucial to know how
activities of STN neurons are regulated.
In slice preparations, STN neurons show rhythmic singlespike activities at resting membrane potentials (Beurrier et al.
1999; Bevan and Wilson 1999; Overton and Greenfield 1995).
This may contribute to the tonic discharge of STN neurons
observed in resting animals (DeLong et al. 1985; Matsumura et
al. 1992; Wichmann et al. 1994a). In response to depolarizing
current pulses, STN neurons increase their firing frequencies
linearly with the magnitude of injected current (Bevan and
Wilson 1999; Nakanishi et al. 1987), suggesting STN neurons
work as linear transformers relaying the strength of inputs
from, for example, the cortex (Magill et al. 2000). STN neurons, however, have intrinsic membrane properties that can
produce more complex firing patterns. In a subset of STN
neurons, the generation of a plateau potential, a long-lasting
depolarizing potential, have been reported in several studies
(Beurrier et al. 1999; Nakanishi et al. 1987; Otsuka et al.
2001a; Overton and Greenfield 1995). The plateau potential
can induce long-lasting high-frequency discharge in the absence of synaptic inputs. One feature of plateau potentials in
STN neurons is the voltage dependence in the generation. STN
neurons can generate a plateau potential only when the cells are
hyperpolarized (Beurrier et al. 1999; Nakanishi et al. 1987;
Otsuka et al. 2001a; Overton and Greenfield 1995). By enabling this feature in the generation of a plateau potential, STN
neurons can transform short-lasting synaptic excitation into
long-lasting burst spikes in a voltage-dependent manner
(Otsuka et al. 2001a) and change their spontaneous activities
from single-spike to burst firing pattern (Beurrier et al. 1999).
In addition, voltage-dependence of a plateau potential may
play important roles in the generation of oscillatory bursting
activity of the STN neurons, characterized by bursts of long
duration and repeating at a low frequency, which correlated
with parkinsonian resting tremor (Bergman et al. 1994; Rodriguez et al. 1998). A recent organotypic culture study has
suggested that the network of the STN and the GP, which are
reciprocally connected, acts as a generator of oscillatory burst
activity of STN neurons (Plenz and Kitai 1999). Because the
STN receives inhibitory inputs from the GP (Groenewegen and
Berendse 1990; Kita et al. 1983b; Moriizumi and Hattori
1992), long-duration bursts in STN neurons may be produced
by long-lasting rebound depolarizations. The plateau potential
in STN neurons, which can be evoked as a rebound potential
(Beurrier
et al. 1999; Otsuka et al. 2001a; Overton and Green-
Address for reprint requests and other correspondence: W.-J. Song, Dept. of
Electronic Engineering, Graduate School of Engineering, Osaka Univ., 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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255
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on June 16, 2017
Otsuka, Takeshi, Takafumi Abe, Takahisa Tsukagawa, and WenJie Song. Conductance-based model of the voltage-dependent generation of a plateau potential in subthalamic neurons. J Neurophysiol 92:
255–264, 2004; 10.1152/jn.00508.2003. Because the subthalamic nucleus (STN) acts as a driving force of the basal ganglia, it is important
to know how the activities of STN neurons are regulated. Previously,
we have reported that a subset of STN neurons generates a plateau
potential in a voltage-dependent manner. These plateau potentials can
be evoked only when the cell is hyperpolarized. Here, to examine the
mechanism of the voltage-dependent generation of the plateau potential in STN neurons, we constructed a conductance-based model of the
plateau-generating STN neuron based on experimental observations
and compared simulation results with recordings in slices. The model
consists of a single compartment containing a Na⫹ current, a delayedrectifier K⫹ current, an A-type K⫹ current, an L-like long-lasting
Ca2⫹ current, a T-type Ca2⫹ current, a Ca2⫹-dependent K⫹ current,
and a leak current. Our simulation results showed that a plateau
potential in the model could be induced in a voltage-dependent
manner that depended on the inactivation properties of L-like longlasting Ca2⫹ current. The model could also reproduce the generation
of a plateau potential as a rebound potential after termination of
hyperpolarizing current injection. In addition, we tested the stability
of simulated plateau potentials against inhibitory perturbation and
found that the model showed similar properties observed for the
plateau potentials of STN neurons in slices. The effects of K⫹ channel
blockade by TEA and intracellular Ca2⫹ ion chelation by BAPTA on
the plateau duration were also tested in the model and were found to
match experimental observations. Thus our STN neuron model could
qualitatively reproduce a number of experimental observations on
plateau potentials. Our results suggest that the inactivation of L-type
Ca2⫹ channels plays an important role in the voltage-dependent
generation of the plateau potential.
256
T. OTSUKA, T. ABE, T. TSUKAGAWA, AND W.-J. SONG
METHODS
that acutely dissociated STN neurons, consisting only of the soma and
proximal dendrites, can generate a plateau potential (Do and Bean
2003). Therefore we constructed the STN model neuron as a single
compartment. The model contains several sets of currents. First, to
produce action potentials, the model includes a sodium current (INa),
potassium currents, and a leak current (Il). Because STN neurons
express Kv3-type and A-type K⫹ currents (IA) as voltage-dependent
K⫹ channels (Wigmore and Lacey 2000), the model contains two
types of K⫹ currents: a delayed rectifier K⫹ current (IK), which has
relatively high activation threshold and fast activation time constant as
features of Kv3-type K⫹ currents (Rudy and McBain 2001), and an
IA, which has low activation threshold and fast activation and inactivation time constants. Second, the model includes L-like long-lasting
Ca2⫹ currents (IL) and low threshold T-type Ca2⫹ currents (IT) as
Ca2⫹ currents. L-type Ca2⫹ channels have been shown to be involved
in the generation of plateau potentials in our previous study (Baufreton et al. 2003; Beurrier et al. 1999; Otsuka et al. 2001a), and the
involvement of IT in the induction of a plateau potential was suggested
by Beurrier et al. (1999). STN neurons also express other types of
high-threshold Ca2⫹ channels such as N- and P/Q-types (Song et al.
2000), but there is no indication that these channels are involved in
plateau potentials, so these were omitted for simplicity. Last, the
model includes Ca2⫹-activated K⫹ current (ICa-K), which has been
observed as a repolarization component of plateau potentials (Otsuka
et al. 2001a). The membrane potential of the plateau-generating STN
model neuron is described by
Whole cell recordings in slice
All experiments were conducted in compliance with the Guidelines
for Use of Laboratory Animals of Osaka University. Slice preparation
including the STN from Sprague-Dawley rats aged P14 –P27 was
obtained with the use of procedures similar to those we have previously described (Otsuka et al. 2001a). Briefly, rats were anesthetized
with ether and decapitated; brains were removed, iced, and blocked
for slicing. The blocked tissue was cut into 350- or 400-␮m-thick
slices with a Microslicer (Dosaka EM) while being bathed in a
high-sucrose solution composed of (in mM) 200 sucrose, 2.5 KCl, 0.5
CaCl2, 10 MgSO4, 1.25 KH2PO4, 26 NaHCO3, and 10 glucose (300 ⫾
5 mOsm/l, pH 7.4). The slices were incubated at room temperature for
ⱖ1 h in oxygenated Kreb’s solution composed of (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).
The slice was transferred to a recording chamber mounted on an
upright microscope (Olympus) and continuously perfused with Kreb’s
solution.
Whole cell recordings from slices employed standard techniques
(Edwards et al. 1989; Stuart et al. 1993). Temperature of the bath
solution in the recording chamber was adjusted to 30°C with a thermo
plate (Tokai Hit). Identification of recorded STN neurons with biocytin was previously described (Otsuka et al. 2001a), and all recoded
neurons were found within the STN in this study. The recording
pipettes were filled with a solution containing (in mM) 70 K2SO4, 30
N-methyl-D-glucamine, 2.5 MgCl2, 35 HEPES, 1.0 EGTA, 0.1 CaCl2,
2 Na2ATP, 0.2 Li2GTP, and 0.1 leupeptin (pH 7.2, 270 ⫾ 5 mOsm/l).
Recordings were obtained with an Axopatch 200B amplifier (Axon
Instruments, Foster City, CA) controlled with a Pentium PC running
pCLAMP (Axon Instruments).
Computer simulation
Previously, we examined the subcellular origin of a plateau potential by taking advantage of a space-clamp problem (Otsuka et al.
2001a). When electrotonically distant synaptic inputs that triggered a
plateau potential in current-clamp mode were activated, generation of
plateau potentials (currents) was prevented by somatic voltage clamp,
suggesting that the subcellular origin of a plateau potential is the soma
and/or proximal dendrites. This notion is supported by the observation
J Neurophysiol • VOL
Cm
dV
⫽ ⫺INa ⫺ IK ⫺ IA ⫺ IL ⫺ IT ⫺ ICa-K ⫺ Il
dt
where Cm is membrane capacitance and takes 1 ␮F/cm2, and V is
membrane potential. The ionic currents are given by the following
Hodgkin-Huxley type equations
I Na ⫽ gNam3h共v ⫺ vNa兲
I K ⫽ gKn4共v ⫺ vK兲
I A ⫽ gIAa2b共v ⫺ vK兲
I L ⫽ gLc2d1d2共v ⫺ vCa兲
I T ⫽ gTp2q共v ⫺ vCa兲
I Ca-K ⫽ gCa-Kr2共v ⫺ vK兲
I l ⫽ gl共v ⫺ vl兲
where a, b, c, d1, d2, h, m, n, p, q, and r are activation or inactivation
variables; VNa, VK, VCa, and Vl are the reversal potentials of the
sodium, potassium, calcium, and leak current, respectively (potentials
in mV); and gNa, gK, gIA, gL, gT, gCa-K, and gl are maximal conductances (in mS/cm2). Because inactivation of L-type Ca2⫹ channel
depends on both voltage and intracellular Ca2⫹ concentration (Imredy
and Yue 1994; Shi and Soldatov 2002; Singer et al. 1991), L-like
long-lasting Ca2⫹ current in our model has two inactivation variables:
voltage- and Ca2⫹-dependent inactivation (d1 and d2, respectively).
VCa is simulated to change with intracellular concentration of Ca2⫹
and is given by the Nernst equation. The extracellular Ca2⫹ concentration of the model cell takes 2 mM to match with our physiological
experiments. Reversal potentials of other ionic currents were assumed
as constants.
The gating kinetics of the ionic conductances are governed by
equations of the following form
dw w⬁共v兲 ⫺ w
⫽
dt
␶w
where w stands for one of a, b, c, d1, d2, h, m, n, p, q, or r; the
steady-state activation and inactivation functions are given by
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field 1995), is one candidate for such potentials. It has also
been shown that GABAA receptor activation can hyperpolarize
STN neurons sufficiently for them to produce rebound burst
firing (Bevan et al. 2000).
Although voltage-dependent generation of a plateau potential in STN neurons has been described in several studies
(Baufreton et al. 2003; Beurrier et al. 1999; Nakanishi et al.
1987; Otsuka et al. 2001a; Overton and Greenfield 1995), the
mechanism of the voltage dependency in the generation of a
plateau potential remains unknown. To explore the mechanism,
we have constructed a model for the plateau-generating STN
neurons, which contains a set of ionic currents identified previously in physiological experiments. We also obtained whole
cell recordings from STN neurons in slices to compare sideby-side with simulation results. Simulation results showed that
our model could reproduce a number of experimental observations on plateau potentials and suggest that the voltagedependent generation of a plateau potential can be attributed to
the inactivation of the L-type Ca2⫹ channel. Some of the
results have been published in abstract form (Otsuka et al.
2000).
CONDUCTANCE-BASED MODEL OF A PLATEAU POTENTIAL
w⬁ ⫽
257
TABLE 1. Basic set of parameter values for the STN
model neuron
1
1 ⫹ exp关共v ⫺ ␪w兲/kw兴
␶ w ⫽ ␶ 0x ⫹ ␶ 1x /兵1 ⫹ exp[⫺(v ⫺ ␪x␶ 兲/␴x)]}
The activation/inactivation time constants of other conductances are
given by the following bell-shaped function
␶ w ⫽ ␶ 0x ⫹ ␶ 1x /兵exp[⫺(v ⫺ ␪x␶1兲/␴1x] ⫹ exp[⫺(v ⫺ ␪x␶2)/␴2x]}
In motoneurons that generate plateau potentials mediated by L-type
Ca2⫹ channels (Kiehn 1991), activation time constant of the L-type
Ca2⫹ current ranges from 30 to several hundreds of milliseconds,
depending on the strength of activation (Schwindt and Crill 1984). We
used an activation time constant ranging from 45 to 55 ms for IL.
Ca2⫹-dependent inactivation time constant of IL was estimated as 130
ms from the observation in myocytes (Findlay 2002). The activation
time constant of ICa-K was set at 2 ms. The activation time constants
of IK ranged from 2 to 5 ms, a feature of Kv3-type K⫹ channels (Rudy
and McBain 2001). Other parameter values used in simulations are
given in Table 1.
Intracellular Ca2⫹ concentration, [Ca]i, depends on the total Ca2⫹
current, ICa, and is given by the following equation
d关Ca兴i
⫽ ⫺␣ICa ⫺ KCa关Ca兴i
dt
␣ ⫽ 1/ZF
where F is the Faraday constant, Z ⫽ 2 is the valence of calcium ion,
and KCa ⫽ 2 ms⫺1 is the Ca2⫹ removal rate. The first term on the right
side has a minus sign, because ICa is minus. In our model, intracellular
Ca2⫹ concentration was 5 nM at rest and reached 70 nM during a
plateau potential.
All simulations reported here were performed using Visual C⫹⫹
(Microsoft). Differential equations were solved by a fourth order
Runge-Kutta algorithm (time step, 0.01 ms).
RESULTS
Firing properties of the STN model neuron
Firing properties of the STN model neuron were adjusted to
experimental observations on slice preparations. In slice preparations, STN neurons showed rhythmic spontaneous spiking
activities at 2-10 Hz (n ⫽ 21/56, Fig. 1A, top; see also Beurrier
et al. 1999; Bevan and Wilson 1999; Overton and Greenfield
1995). The model neuron fires spontaneously at ⬃10 Hz (Fig.
1A, bottom). Action potentials in the model were repolarized
quickly, and membrane potentials were depolarized to the
J Neurophysiol • VOL
Parameter
gNa
gK
gIA
gL
gT
gCa-K
gl
VNa
VK
Vl
␪a
␪b
␪c
␪d1
␪d2
␪m
␪h
␪n
␪p
␪q
␪r
ka
kb
kc
kd1
kd2
kr
Value
Parameter
Value
49
57
5
15
5
1
0.35
60
⫺90
⫺60
⫺45
⫺90
⫺30.6
⫺60
0.1
⫺40
⫺45.5
⫺41
⫺56
⫺85
0.17
⫺14.7
7.5
⫺5
7.5
0.02
⫺0.08
␶ ,␶
␶ ,␶
␶ ,␶
␶ ,␶
␶ ,␶
␶ ,␶
␶ ,␶
␶ ,␶
␶ ,␶
␪
␪ , ␪ b␶2
␪ , ␪ c␶2
␶2
␪ , ␪ d1
␪
␪ , ␪ h␶2
␪ , ␪ n␶2
␪ , ␪ p␶2
␪ , ␪ q␶2
␴a
␴ 1b, ␴ 2b
␴ c1, ␴ c2
␴ 1d1, ␴ 2d1
␴m
␴ 1h, ␴ 2h
␴ 1n, ␴ 2n
␴ 1p, ␴ 2p
␴ 1q, ␴ 2q
1, 1
0, 200
45, 10
400, 500
0.2, 3
0, 24.5
0, 11
5, 0.33
0, 400
⫺40
⫺60, ⫺40
⫺27, ⫺50
⫺40, ⫺20
⫺53
⫺50, ⫺50
⫺40, ⫺40
⫺27, ⫺102
⫺50, ⫺50
⫺0.5
⫺30, 10
⫺20, 15
⫺15, 20
⫺0.7
⫺15, 16
⫺40, 50
⫺10, 15
⫺15, 16
0
a
0
b
0
c
0
dl
0
m
0
h
0
n
0
p
0
q
␶
a
␶1
b
␶1
c
␶1
d1
␶
m
␶1
h
␶1
n
␶1
p
␶1
q
1
a
1
b
1
c
1
dl
1
m
1
h
1
n
1
p
1
q
threshold of spikes following a slow hyperpolarization, similar
to those in the STN neurons (Fig. 1A, insets). Figure 1B
displays the individual ionic currents (bottom) during spontaneous activity of the model. Rhythmic spontaneous activities
of the model are driven largely by INa. The fast upstroke of the
action potential in the model is driven by INa (Fig. 1C) (Do and
Bean 2003). After activation of INa, IK activates immediately to
repolarize the potential. Although Ca2⫹ and Ca2⫹-dependent
K⫹ currents contribute little during interspike interval and
action potential, manipulation of maximal conductances of
these currents affects the frequency of spontaneous activities
(data not shown). In response to depolarizing current pulse
injection, STN neurons fired repetitively ⱕ100 Hz (n ⫽ 5, Fig.
1D, left). Firing frequency increased in a near-linear manner
with the increase of the magnitude of current pulse (Fig. 1E,
top) (Bevan and Wilson 1999; Nakanishi et al. 1987). In the
STN model neuron, injection of depolarizing current pulse
induced repetitive action potentials during current injection.
Increase of the current intensity induced high-frequency spikes
during current injection (Fig. 1D, right). The relationship between firing frequency and current intensity of the model
neuron is close to linear (Fig. 1E), similar to that observed in
slice preparations. Thus our STN model neuron qualitatively
reproduces the characteristics of spontaneous spiking activity
and spiking responses to depolarizing current pulse injection at
the resting membrane potential.
Voltage-dependent generation of a plateau potential
A plateau potential can be induced in STN neurons that are
hyperpolarized (Beurrier et al. 1999; Nakanishi et al. 1987;
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where ␪w and kw are the half-activation/half-inactivation voltage and
slopes, respectively. In the case of d2 (Ca2⫹-dependent inactivation
variable of IL) and r (Ca2⫹-dependent K⫹ conductance), steady-state
inactivation and activation depend on intracellular Ca2⫹ concentration
(in ␮M). In Xenopus oocytes, half-inactivation voltage for voltagedependent inactivation of L-like long-lasting current ranged from –68
to –62 mV, depending on the expression of subunits (Singer et al.
1991). We assumed half-inactivation voltage of L-like long-lasting
Ca2⫹ currents to be –60 mV. Half-inactivation Ca2⫹ concentration of
Ca2⫹-dependent inactivation was assumed to be 100 nM (Ohya et al.
1988). Half-activation voltage of IK was set according to values
obtained in STN neurons (Wigmore and Lacey 2000). Kinetics of IA
was modified from data obtained in striatal cholinergic interneurons
(Song et al. 1998). Half-activation and inactivation voltages of IT took
values obtained in brain slice (Perez-Reyes 2003). The activation time
constants (␶w in ms) for INa and IA, which have fast onset kinetics, are
given by the following sigmoidal function
258
T. OTSUKA, T. ABE, T. TSUKAGAWA, AND W.-J. SONG
A
B
experiment
C
30 mV
15 msec
30 mV
30 mV
20 mV
-60 mV
0.2 sec
15 msec
0.1 sec
model
30 mV
0
0
15 msec
20 mV
-60 mV
40 uA/cm2
4 uA/cm2
0.2 sec
0.5 sec
spikes / sec
0.5 sec
60 mV
steady state
100
1
1
0.5
0.5
50
0
60 mV
F
experiment
150
0
50
100
150
current intensity (pA)
200
model
100
100
( uA/cm2 )
E
model
spikes / sec
experiment
0
-100 -50 0
mV
1sec
0
0
-60
100
nM
200
-40
-70
-100
50
0
50
-50
0
0
2
4
6
2
current intensity ( uA/cm )
1
time (sec)
1.5
FIG. 1. Properties of the subthalamic nucleus (STN) model neuron. A: spontaneous activities of the STN and model neuron.
STN neurons showed rhythmic spiking activities. The model neuron also produces rhythmic spontaneous activities. Insets:
magnification of action potentials obtained in spontaneous activities of the STN neuron and the model. B: individual ionic currents
contributing to spontaneous activities of the model. Top: spontaneous activities of the model. Bottom: ionic currents during
spontaneous activities (black thick solid, INa; black solid, IL; black dashed, IT; gray thick solid, IK; gray solid, IA; gray dashed,
IK-Ca). C: ionic currents during an action potential. Top: an action potential. Bottom: individual ionic currents during the action
potential. Each line shows same current as in B. D: responses of STN and model neurons to depolarizing current pulse injections
(duration 1 s; intensity 10, 50, and 100 pA in STN neuron, 0.5, 2, and 6 in the model). Firing frequency increased with increase
of current intensity. E: relationships between current intensity and firing frequency of a STN and the model neuron. F: simulated
current-voltage relations obtained in the model. Currents were evoked by ramp-shape voltage change preceded by 1-s prepulse to
– 60 or –100 mV. Negative currents are obtained when –100-mV prepulse was used. Na⫹ conductance was set to 0. Inset:
steady-state activation and inactivation of L-like long-lasting Ca2⫹ conductance.
Otsuka et al. 2001a; Overton and Greenfield 1995). In principle, generation of a plateau potential requires the steady-state
current-voltage (I-V) curve to cross zero current with a negative slope (Kiehn 1991). Therefore for a plateau potential to
occur in a voltage-dependent manner as it does in STN neurons, the steady-state I-V curve of the cell must cross zero
current with a negative slope only when the cell is held at
hyperpolarized state; namely, the channels giving rise to this
current have to 1) decay slowly to maintain a plateau potential,
2) be inactivated at the resting membrane potential, and 3) be
deinactivated at hyperpolarized potentials. The L-type Ca2⫹
channel, which is involved in the generation of a plateau
potential in STN neurons (Baufreton et al. 2003; Beurrier et al.
1999; Otsuka et al. 2001a), is one candidate for such a conductance, because of its slow inactivation kinetics. We therefore examined whether voltage-dependent generation of plateau potentials in the STN model neuron depends on inactivation properties of L-like long-lasting Ca2⫹ conductance.
Because inactivation of L-type Ca2⫹ channels depends on both
voltage and Ca2⫹ (Imredy and Yue 1994; Shi and Soldatov
J Neurophysiol • VOL
2002; Singer et al. 1991), our L-like long-lasting Ca2⫹ current
model includes both voltage- and Ca2⫹-dependent inactivation
variables. In the presence of inactivation of the long-lasting
Ca2⫹ conductance (Fig. 1F, insets), currents evoked by a slow
voltage ramp had a negative slope region, but only when the
model was held at hyperpolarized potentials before the ramp
protocol (Fig. 1F). No voltage dependence of the negative
slope was observed when the inactivation was removed. Thus
inclusion of the inactivation variable to the L-like long-lasting
Ca2⫹ current allows the model to change the shape of the
steady-state I-V curve in a voltage-dependent manner.
We then examined whether our STN model could reproduce
voltage-dependent generation of a plateau potential by comparing the responses of the model to injection of depolarizing
current pulses at the resting and hyperpolarized membrane
potentials with those of plateau-generating STN neurons. We
recorded from 56 STN neurons. Twenty-seven STN neurons
were plateau-generating neurons, and 15 of them generated
repetitive action potentials during a plateau potential. Examples of recordings from a plateau-generating STN neuron are
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D
CONDUCTANCE-BASED MODEL OF A PLATEAU POTENTIAL
B
experiment
A
-60 mV
model
Generation of a plateau potential as rebound potentials
-58 mV
20 mV
20 mV
0.2 sec
0.3 sec
-77 mV
-75 mV
normalized frequency
C
STN neuron
model
1
0.5
0
0
10
20
ating STN neurons, decrease of firing frequency during a
plateau potential in the model is similar to those in STN
neurons (Fig. 2C). When the inactivation variable of IL was
removed from the model, no voltage dependency of the generation of plateau potentials was observed (data not shown).
These results suggest that inactivation of L-type Ca2⫹ channels
plays an important role in the voltage-dependent generation of
a plateau potential.
We next compared the voltage-dependence of the generation
of plateau potentials in the model with that of plateau-generating STN neurons. For this purpose, membrane potentials of
the STN neurons and the model were gradually hyperpolarized
by changing the amounts of injected constant currents, while a
depolarizing current pulse was injected to test whether a plateau potential could be induced. Examples of responses of a
STN neuron to current pulse injection are shown in Fig. 3A.
Plateau potentials in STN neurons were triggered when membrane potential was below –70 mV (n ⫽ 5). In the model,
plateau potentials developed within a similar range of membrane potentials (Fig. 3B). The relationship between plateau
duration, defined as the duration from the pulse end to the time
when membrane potential returned to the baseline level, and
membrane potential is shown in Fig. 3C. Development of
plateau potentials in STN neurons and the model showed
similar behavior. Thus our model qualitatively reproduces the
voltage-dependent generation of a plateau potential in STN
neurons.
30
40
spike number
FIG. 2. Voltage-dependent generation of a plateau potential. A: recordings
from a plateau-generating STN neuron. Top: injection of a depolarizing current
pulse (50 pA, bottom), at the resting membrane potentials, induced repetitive
action potentials during the pulse. Middle: injection of same current pulse, at
hyperpolarized potentials, evoked a plateau potential with burst spikes. B:
responses of the STN model neuron to current pulse injection (5 ␮A/cm2,
bottom). At the resting membrane potentials, current injection induces repetitive action potentials during the pulse (top). Middle: injection of same current
pulse, at a hyperpolarized state, evoked a plateau potential with burst spikes,
which outlasted current injection. Membrane potentials of both STN neuron
and model neuron were controlled by constant current injection. C: relation
between firing frequency and spike number during a plateau potential in STN
neurons and the model neuron. Firing frequencies were normalized against
maximal frequency. Frequencies of the STN neurons were averaged from 10
plateau-generating neurons. Error bar shows confidence interval.
J Neurophysiol • VOL
Another feature of the voltage-dependent generation of a
plateau potential is that a plateau potential can be evoked as a
rebound potential after termination of negative current injection (Beurrier et al. 1999; Nakanishi et al. 1987; Otsuka et al.
2001a; Overton and Greenfield 1995). Because the equilibrium
potential of GABAA receptors in STN neurons is lower than
the threshold potential of a plateau potential (Bevan and Wilson 1999), a volley of inhibitory inputs to STN neurons would
be expected to induce a plateau potential as rebound potentials.
Therefore generation of a plateau potential as rebound potentials might be an important physiological property of STN
neurons, considering that these cells receive massive inhibitory
inputs from the GP (Groenewegen and Berendse 1990; Kita et
al. 1983b; Moriizumi and Hattori 1992). We thus examined
whether our model can reproduce the generation of a plateau
potential as rebound potentials.
Examples of rebound responses recorded from a plateaugenerating STN neuron are shown in Fig. 4A. When the amplitude of the hyperpolarizing current was kept constant, the
generation of a plateau potential was directly related to the
duration of the current pulse. Injection of a short-duration
current pulse (100 ms, ⫺50 pA) induced rebound potentials of
small amplitude and short duration (Fig. 4A, top). An increase
of the duration of the current pulse, however, induced long
duration rebound plateau potentials with burst discharges (Fig.
4A, middle). The duration of the plateau potential became
longer with further increase in the duration of current pulses
(Fig. 4A, bottom). Sufficient duration of negative current pulse
(intensity, ⫺50 pA), which triggered a rebound plateau potential, ranged from 100 to 200 ms (n ⫽ 9). These behaviors were
qualitatively reproduced in the model. Generation of a plateau
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shown in Fig. 2A. At the resting membrane potential, injection
of depolarizing current pulses evoked repetitive action potentials during current injection (Fig. 2A, top). Spontaneous rhythmic spiking activities were also observed before and after
injection of current pulse. When the cell was hyperpolarized by
injection of constant currents, spontaneous activities disappeared. At hyperpolarized potentials, injection of current pulse
induced a plateau potential with burst firing, which outlasted
current injection (Fig. 2A, bottom). In the model, injection of
depolarizing current pulse similarly evokes repetitive action
potentials during current injection at the resting membrane
potentials, and spontaneous rhythmic activities remain before
and after current injection (Fig. 2B, top). When the model is
hyperpolarized by injection of constant current, spontaneous
activities disappear as observed in slice preparations. At hyperpolarized states, a plateau potential with burst firing is
elicited that outlasted current injection in the model neuron,
similar to those in STN neurons (Fig. 2B, bottom). Maximal
firing frequencies of STN neurons and the model after current
injection were 61.5 ⫾ 6.69 (n ⫽ 15) and ⬃150 Hz, respectively. Although firing frequencies during plateau potentials
are somewhat different between our model and plateau-gener-
259
T. OTSUKA, T. ABE, T. TSUKAGAWA, AND W.-J. SONG
experiment
-40
-60
-80
B
model
membrane potential (mV)
membrane potential (mV)
A
-40
-60
-80
-40
-60
-80
-40
-60
-80
C
-40
-60
-80
model
STN neuron
-40
membrane potential (mV)
260
-40
-60
-80
-40
-60
-80
-40
-60
-80
-50
-60
-70
-80
-90
0
0.2 sec
0.5 sec
0.5
1.0
normalized duration
potential as a rebound potential depends on the duration of a
hyperpolarizing current pulse (Fig. 4B). Here, spontaneous
spiking activity was suppressed by injecting a small amount of
hyperpolarizing constant current (⫺1.5 ␮A/cm2) to the model
A
B
experiment
model
-60.7 mV
-63 mV
40 mV
40 mV
0.5 sec
to obtain a clear rebound response. Rebound plateau potentials
in the model, however, were triggered by negative current
pulse of shorter duration than that in STN neurons. When
hyperpolarizing current pulse was injected at resting membrane
potentials in the absence of negative constant current, spiking
frequencies of rebound responses gradually decreased following a long-lasting burst and returned to the rate of spontaneous
firing in both the model and STN neurons (Fig. 4, C and D).
The above results suggest that plateau potentials induced as a
rebound potential in the model are qualitatively similar to those
induced in STN neurons.
0.2 sec
Stability of a plateau potential
C
D
experiment
model
30 mV
30 mV
-57 mV
-58 mV
0.5 sec
0.5 sec
FIG. 4. Generation of a plateau potential as a rebound potential. A: rebound
responses of a plateau-generating STN neuron after hyperpolarizing current
pulses of various durations (bottom: currents). Plateau potentials were evoked
after termination of current injection and the duration depended on the duration
of hyperpolarizing current pulse. B: responses of the STN model neuron to
different duration current pulses. Generation and duration of a plateau potential
depends on the duration of hyperpolarizing current pulse as in STN neurons.
To block spontaneous activities, ⫺1.5-␮A/cm2 constant current was injected to
the model. Top: spikes were shown only for a part to better show subthreshold
potentials. C and D: rebound responses of the STN neuron and the model to
hyperpolarizing current pulse injection (0.5 s, ⫺50 pA for STN neuron; ⫺5
␮A/cm2 for the model). Firing frequencies of rebound responses were decreased gradually and returned to spontaneous firing rate.
J Neurophysiol • VOL
Previously, we have shown that the early part of a plateau
potential in STN neurons is resistant to inhibitory perturbations, but the late part is not (Otsuka et al. 2001a). Because
STN receives inhibitory inputs from the GP (Groenewegen and
Berendse 1990; Kita et al. 1983b; Moriizumi and Hattori
1992), the stability of a plateau potential against inhibitory
inputs would be important to shape the firing pattern of STN
neurons in vivo. Therefore we examined whether the plateau
potential in our model shows similar stability to that observed
experimentally, as in our previous study (Otsuka et al. 2001a).
To this end, we simulated an inhibitory synaptic current by
injecting negative current pulse (20 ms, ⫺10 ␮A/cm2) in the
model at various times during the course of the plateau potential (Fig. 5A). Plateau potentials were induced by injection of a
depolarizing current pulse (20 ms, 5 ␮A/cm2) at a hyperpolarized state. Na⫹ conductance was set to 0 mS/cm2 to suppress
action potentials. The stability was estimated, as in our previous experiments (Otsuka et al. 2001a), by the ratio of the
potential after the negative current pulse to the potential before
the current, defined as the stability index. The stability index of
a stable potential equals to one. Shown in Fig. 5B is the
transition of the stability index of a plateau potential, estimated
at various times during the course of the plateau potential of the
model. The stability index was close to one during the early
phase of the potential and decreased slowly. At late phase of
the plateau potential, the stability index decreased quickly and
took negative values toward the end of the potential (Fig. 5B,
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FIG. 3. Voltage dependence of the induction of a plateau potential. A and B: responses of STN and model neuron to current pulse
injections (50 ms, 50 pA, 5 ␮A/cm2). STN and model neuron were held at different membrane potentials by injecting constant
currents. C: relations between holding membrane potentials and plateau duration in STN neuron (E) and the model (F). Plateau
durations of the STN and the model neuron were normalized against maximal plateau durations, respectively.
CONDUCTANCE-BASED MODEL OF A PLATEAU POTENTIAL
A
the rate of Ca2⫹ chelation. Increasing the value of X leads to
increases in the duration of a plateau potential (Fig. 6C). This
effect, however, is saturated at a duration around 1.3 times the
initial duration (Fig. 6D). Thus our model reproduces the
effects of Ca2⫹ chelation and K⫹ channel blocking on plateau
duration, suggesting that ionic mechanisms of plateau potential
repolarization in the model are the same as those in STN
neurons.
20 mV
0.15 sec
B
2
-20 uA/cm
2
-10 uA/cm
1
DISCUSSION
0
0.2
0.4
0.6
0.8
1
FIG. 5. Stability of a plateau potential in the STN model neuron. A: plateau
potentials were induced from a hyperpolarized state (⫺76 mV) with a current
pulse (20 ms, 5 ␮A/cm2). After induction of plateau potentials, a hyperpolarizing current pulse (20 ms, ⫺10 ␮A/cm2) was applied at various times during
the plateau potential. Membrane potentials were hyperpolarized by injection of
constant current. Na⫹ conductance was set to 0 mS/cm2. B: ratio of the value
of membrane potentials after the negative current pulse to the potential before
the current injection was plotted against normalized plateau potential duration.
F). Doubling the amount of injected negative current pulse did
not affect the stability index of a plateau potential at the early
phase but shifted the decrease of stability index left (Fig. 5B,
E). These stability properties of a plateau potential are consistent with the experimental observations (Otsuka et al. 2001a).
When the negative current pulse was injected to the model
during a plateau potential with burst (gNa ⫽ 48), burst firing
was resistant to the current pulse injection, except during a late
part of plateau potentials (data not shown). Thus our model
reproduces not only behaviors of plateau generation but also
the nature of a plateau potential on inhibitory perturbations.
We have previously shown that chelation of intracellular
Ca2⫹ by bis-(o-aminophenoxy)-N,N,N⬘,N⬘-tetraacetic acid
(BAPTA), applied through the patch pipette, or bath-application of the K⫹ channel blocker, tetraethylammonium chloride
(TEA), enhanced the duration of a plateau potential (Otsuka et
al. 2001a). To confirm the validity of our plateau-generating
STN model neuron, we examined whether the model reproduces these effects.
The effects of TEA were simulated by decreasing the value
of maximal delayed-rectifier type K⫹ conductance (gK). Decreasing the value of gK increases the duration of plateau
potentials (Fig. 6, A and B). When gK was set to 1 mS/cm2, the
plateau potential lasted about 1.8 times the initial duration. In
addition, the peak of a plateau potential is also elevated with
the decrease of gK. These effects are consistent with those
observed in our previous experiments (Otsuka et al. 2001a).
To simulate the effect of Ca2⫹ chelation by BAPTA, we
divided the Ca2⫹ flux by a scalar, X, called the rate of Ca2⫹
chelation. Intracellular Ca2⫹ concentration was represented by
the following equation
d关Ca兴i
␣ICa
⫽⫺
⫺ KCa关Ca兴i
dt
X
The duration of a simulated plateau potential was sensitive to
J Neurophysiol • VOL
We constructed a model of plateau-generating STN neurons
with a single compartment containing Na⫹ current, Kv3-like
high-threshold delayed rectifier K⫹ current, A current, L-like
long-lasting Ca2⫹ current, T-type Ca2⫹ current, Ca2⫹-dependent K⫹ current, and leak current. Although our model shows
a variety of firing behaviors resembling those observed in
physiological experiments, it does not constitute a physiologically complete description of STN neurons. Ionic currents
having less obvious relationships with plateau potentials were
C
A
mV
Reproduction of experimental pharmacological observations
Conductance of STN neurons
0
0
-20
-20
-40
-60
-80
-40
-60
-80
0.1 sec
0.1 sec
B
D
60
10
50
40
30
20
8
6
4
2
10
0
1
1.5
normalized plateau duration
2
0
1
1.1
1.2
1.3
normalized plateau duration
2⫹
FIG. 6. Simulated effects of TEA and intracellular Ca
chelation. A:
superimposed voltage traces to current pulse injections, with decreasing delayed rectifier type K⫹ conductance. The value of gK was set to 50, 40, 30, or
20 mS/cm2. Membrane potentials of the model were hyperpolarized by injection of constant currents (⫺6.5 ␮A/cm2) for plateau potentials to occur. B:
relation of plateau duration and K⫹ conductance. Decrease of K⫹ conductance
increased the duration of plateau potential. C: plateau potentials evoked by
current pulse injections. Ca2⫹ currents were divided by constants to mimic the
effect of Ca2⫹ chelation. Membrane potentials were hyperpolarized by constant current injection. Chelation rate, X, was set to 1, 2.5, 5, or 10. D: relation
of plateau duration and the chelation rate. Increase of chelation rate increased
the plateau duration but increase of the plateau duration was saturated. Na⫹
conductance was set to 0 mS/cm2 to block action potentials in both A and C.
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normalized plateau duration
mV
0
In this study, we investigated the mechanism of the voltagedependent generation of a plateau potential in STN neurons
with computer simulations. Voltage-dependent generation of a
plateau potential in STN neurons could be reproduced with the
inactivation variable of L-like long-lasting Ca2⫹ current. Simulation results showed that our STN model neuron could reproduce a number of experimental observations on plateau
potentials. Inactivation of L-type Ca2⫹ channel may play important roles in the voltage-dependent generation of a plateau
potential in STN neurons.
chelation rate
0.5
conductance (mS/cm 2)
post / pre-pulse voltage
261
262
T. OTSUKA, T. ABE, T. TSUKAGAWA, AND W.-J. SONG
Conductance of the STN model neuron
Previous studies of the STN model have focused on the
network behavior of the STN and the GP (Gillies et al. 2001;
Humphries and Gurney 2001; Terman et al. 2002). They presented STN model neurons as the integrate-and-fire neuron
(Humphries and Gurney 2001) or the model where spikes were
convolved with an ␣-type response functions (Gillies et al.
2001), for simplicity. Terman et al. (2002) have also constructed an STN model with Hodgkin-Huxley type equations
and have elegantly simulated a number of activity patterns in a
modeled STN-GP network. The firing behavior at resting
membrane potentials, the firing response to current injection, as
well as a long-lasting rebound potential in STN neurons were
also simulated in Terman et al. (2002). In this study, we
focused on simulating the voltage-dependent generation of
plateau potentials and rebound potentials in STN neurons and
provided a side-by-side comparison of experimental results and
simulation results. Long-lasting rebound potentials were simulated with T-type Ca2⫹ currents in Terman et al. (2002),
J Neurophysiol • VOL
whereas in our model, L-type currents play an essential role in
the voltage-dependent generation of plateau potentials and
long-lasting rebounds. We modeled plateau potentials with
L-type currents because of experimentally shown sensitivity of
plateau potentials to dihydropyridines (Baufreton et al. 2003;
Beurrier et al. 2000; Otsuka et al. 2001a). Although the STN
consists only of projection neurons (Kitai and Kita 1987), STN
neurons can be divided into two cell groups, namely, plateaugenerating and non–plateau-generating neurons (Otsuka et al.
2001a). Non–plateau-generating neurons can also generate rebound potentials after termination of hyperpolarizing current
injection (Otsuka et al. 2001a). These rebound potentials, however, were terminated within 100 ms and mediated by T-type
currents (Beurrier et al. 1999; Song et al. 2000).
All ionic conductances included in the plateau-generating
STN model described here are those obtained from physiological experiments. Because the kinetic parameters of conductances of STN neurons remain unknown, the values of these
parameters were assigned. In our model, generation of a plateau potential is mediated by L-like long-lasting Ca2⫹, Kv3type K⫹, and Ca2⫹-dependent K⫹ currents, which were identified experimentally in our previous study (Otsuka et al.
2001a). Kv3 channels in STN neurons, characterized in slice
preparations, activate at around ⫺40 mV, with half-activation
voltage around ⫺15 mV (Wigmore and Lacey 2000). Our Kv3
current model also activates at around ⫺40 mV, with a halfactivation voltage of ⫺17.5 mV. Expression of apamin-sensitive Ca2⫹-activated K⫹ current has been described in STN
neurons (Bevan and Wilson 1999). The apamin-sensitive
Ca2⫹-activated K⫹ channel is activated by submicromolar
Ca2⫹ (Rudy 1988). Our Ca2⫹-activated K⫹ current model
activates with a half-activation of 240 nM Ca2⫹. Thus our
parameter values for K⫹ currents used here are biophysically
plausible. Among high-threshold Ca2⫹ channels in STN neurons, L-type channels activate from lowest voltages, with a
half-activation voltage of –20 mV (Song et al. 2000). Here we
modeled L-like long-lasting Ca2⫹ channels with –25 mV for
half-activation voltage. The observations in acutely dissociated
preparations, however, were obtained with Ba2⫹ as the charge
carrier. Because activation and inactivation properties of Ca2⫹
channels depend on the species and concentration of charge
carrier (Bargas et al. 1994; Lorenzon and Foehring 1995),
physiological values of Ca2⫹ channel parameters of STN neurons remain unknown. Among L-type channels, Cav 1.3 channels activate from lower voltages (Xu and Lipscombe 2001),
with half-activation voltage ranging from – 40 to –20 mV,
depending on concentration of charge carriers. Currently it is
not known which subtypes of L-type channels are expressed in
STN neurons. In this study, we used parameter values for
voltage- and Ca2⫹-dependent inactivation obtained from experiments in other cells (Ohya et al. 1988; Singer et al. 1991).
It must be pointed out, however, that currently there is conflicting experimental evidence on voltage-dependent inactivation of L-type channels; whereas some report little inactivation
(Xu and Lipscombe 2001), others find full inactivation (Singer
et al. 1991). The inactivation behavior of L-type channels in
STN neurons remains to be determined. In the model, dependency of plateau generation as a rebound potential on hyperpolarizing current pulse injection was somewhat different from
that in the STN neuron (see Fig. 4). This difference may in part
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not included in our model. Nevertheless, our model qualitatively reproduced similar firing behavior and plateau potentials
observed in our slice experiments (Otsuka et al. 2001a). Conductances that have been physiologically identified in STN
neurons but not considered in our model include TTX-sensitive
sustained Na⫹ current (INaP) (Beurrier et al. 2000; Bevan and
Wilson 1999), a hyperpolarization-activated inward current
(Ih) (Song et al. 2000), and several types of high-threshold
Ca2⫹ channels (Song et al. 2000). These channels may contribute to the voltage-dependent generation of a plateau potential. INaP can impart a negative slope region to the steady-state
I-V curve of STN neurons (Beurrier et al. 2000; Bevan and
Wilson 1999). However, INaP appears not essential for plateau
generation, because the plateau potential in STN neuron could
be evoked in the presence of TTX (Baufreton et al. 2003;
Beurrier et al. 1999; Otsuka et al. 2001a). TTX-sensitive subthreshold membrane oscillations were observed in STN neurons (Otsuka et al. 2001a). INaP may contribute to the rhythm
of spontaneous spiking activities as in type I neurons of the
tegmental pedunculopontine nucleus (Bevan and Wilson 1999;
Do and Bean 2003; Takakusaki and Kitai 1997). Because Ih
activates with hyperpolarization and deactivates slowly (McCormick and Pape 1990), it may be involved in the generation
of a plateau potential in STN neurons in a voltage-dependent
manner. However, bath-applied low concentration of Cs⫹ or
ZD 7288, a specific Ih blocker (Harris and Constanti 1995), did
not prevent the generation of a plateau potential (unpublished
data). Furthermore, when the model included Ih instead of IL,
plateau potentials could not be induced at hyperpolarized state,
although long-lasting rebound depolarizations occurred. These
observations suggest that Ih does not play an important role in
the voltage-dependent generation of a plateau potential in STN
neurons. Plateau potentials in STN neurons decayed at a lower
rate compared with simulated plateau potentials in our model
(see Fig. 2). Repolarization kinetics of a plateau potential may
be regulated not only by the inactivation of L-type Ca2⫹
channels and the activation of Ca2⫹-dependent K⫹ channels,
but also by the deactivation of Ih. In addition, Ca2⫹-dependent
cation channels may also slow the decay of a plateau potential
(Beurrier et al. 1999).
CONDUCTANCE-BASED MODEL OF A PLATEAU POTENTIAL
be attributable to possible difference in recovery kinetics of
L-type channels in STN neurons and in our model.
Even if L-type Ca2⫹ channels activate at low voltages,
currents mediated by Ca2⫹ channels would be small during a
plateau potential. STN neurons express a Kv3-type delayed
rectifier and an A current (IA) as depolarization-activated K⫹
channels (Weiser et al. 1994; Wigmore and Lacey 2000). The
high threshold of activation of Kv3 channels (Rudy and
McBain 2001) and the fast inactivation of IA (Rudy 1988)
would make STN neurons have high-input resistances at potentials close to resting, enabling the generation of a plateau
potential by small amounts of inward currents.
STN-GP circuit
J Neurophysiol • VOL
ACKNOWLEDGMENTS
We thank J. Wesseling and A. Horton for helpful comments on the manuscript.
Present address of T. Otsuka: Department of Neurobiology, Duke University
Medical Center, Durham, NC 27710.
GRANTS
This work was supported by the Uehara Foundation and Grants-in-Aid for
Scientific Research on Priority Areas (15500213, 15029228, and 15016065)
from the Ministry of Education, Science, and Culture, Japan to W.-J. Song.
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Oscillatory long-duration burst activity in STN neurons has
been the subject of an increasing number of studies, because
this activity correlates with parkinsonian resting tremor (Bergman et al. 1994; Rodriguez et al. 1998). In the study of
organotypic slice culture, it has been suggested that the network of the STN and the GP, which forms a recurrent excitatory–inhibitory interaction, acts as a generator of oscillatory
bursting activities (Plenz and Kitai 1999). Oscillatory bursting
activities in STN neurons are either in-phase or anti-phase with
those in GP neurons (Plenz and Kitai 1999). Because STN
receives inhibitory inputs from the GP, STN must generate
long-duration depolarizing potentials as a rebound potential to
induce long-duration burst. Voltage-dependent generation of a
plateau potential in STN neurons, which can be evoked as a
rebound potential, would be one candidate for such potentials.
A rebound plateau potential has been suggested to occur in
type I cerebellar nuclei neuron, in response to strong inhibition
from Purkinje cells (Czubayko et al. 2001). Recent computer
modeling studies have shown that oscillatory bursting activities
could be reproduced in a modeled STN-GP circuit (Gillies et
al. 2001; Humphries and Gurney 2001; Otsuka et al. 2001b;
Terman et al. 2002). In a modeled STN-GP circuit, oscillatory
activities are due to rebound responses mediated by Ca2⫹
current in STN neurons (Humphries and Gurney 2001; Otsuka
et al. 2001b). In addition, both in-phase and anti-phase oscillatory bursts were reproduced in a modeled network of plateaugenerating STN and GP neurons (Otsuka et al. 2001b). Thus
plateau potentials in STN neurons may play important roles in
generating oscillatory bursting activities.
Given that oscillations are due to long-duration rebound
responses in STN neurons, what causes STN neurons to switch
activity patterns to the oscillation? Why is oscillatory bursting
activity only observed in parkinsonian, but not normal, subjects? Recent evidence suggests that membrane potentials of
STN neurons are depolarized by dopamine application (Zhu et
al. 2002). STN neurons in normal subjects would be depolarized by dopamine, and thus GP inhibitory inputs would not
hyperpolarize STN neurons enough for plateau potentials to be
induced. After dopamine depletion, because Parkinson’s disease is caused by dopamine depletion, the membrane potential
of STN neurons in affected patients would be hyperpolarized;
therefore a plateau potential would be more likely to be induced in STN neurons, resulting in oscillatory bursting activities.
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