1Laboratoire de neurophysiologie, Centre National de la Recherche Scientifique, 33076 Bordeaux Cedex; and 2Institut National de la Santé et de la Recherche Médicale U29, Institut de Neurobiologie de la Mediterranée, 13273 Marseille Cedex 09, France
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ABSTRACT |
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Beurrier, Corinne,
Bernard Bioulac, and
Constance Hammond.
Slowly Inactivating Sodium Current
(INaP) Underlies Single-Spike Activity in
Rat Subthalamic Neurons.
J. Neurophysiol. 83: 1951-1957, 2000.
One-half of the subthalamic nucleus (STN) neurons switch from
single-spike activity to burst-firing mode according to membrane potential. In an earlier study, the ionic mechanisms of the bursting mode were studied but the ionic currents underlying single-spike activity were not determined. The single-spike mode of activity of STN
neurons recorded from acute slices in the current clamp mode is
TTX-sensitive but is not abolished by antagonists of ionotropic glutamatergic and GABAergic receptors, blockers of calcium currents (2 mM cobalt or 40 µM nickel), or intracellular Ca2+ ions
chelators. Tonic activity is characterized by a pacemaker depolarization that spontaneously brings the membrane from the peak of
the afterspike hyperpolarization (AHP) to firing threshold (from
57.1 ± 0.5 mV to
42.2 ± 0.3 mV). Voltage-clamp
recordings suggest that the Ni2+-sensitive, T-type
Ca2+ current does not play a significant role in
single-spike activity because it is totally inactivated at potentials
more depolarized than
60 mV. In contrast, the TTX-sensitive,
INaP that activated at
54.4 ± 0.6 mV
fulfills the conditions for underlying pacemaker depolarization because
it is activated below spike threshold and is not fully inactivated in
the pacemaker range. In some cases, the depolarization required to
reach the threshold for INaP activation is
mediated by hyperpolarization-activated cation current
(Ih). This was directly confirmed by the
cesium-induced shift from single-spike to burst-firing mode which was
observed in some STN neurons. Therefore, a fraction of
Ih which is tonically activated at rest,
exerts a depolarizing influence and enables membrane potential to reach the threshold for INaP activation, thus
favoring the single-spike mode. The combined action of
INaP and Ih is
responsible for the dual mode of discharge of STN neurons.
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INTRODUCTION |
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The subthalamic nucleus (STN) is a basal ganglia
nucleus that plays an important role in normal (Matsumara et al.
1992; Wichmann et al. 1994
) and pathological
(Bergman et al. 1994
) motor behavior. By way of its
glutamatergic projections (Smith and Parent 1988
), STN
imposes its rhythm to the two principal output structures of the basal
ganglia, the internal pallidal segment and the substantia nigra pars
reticulata (Féger et al. 1997
; Parent and
Hazrati 1995
). In a normal in vivo situation, the great
majority of rat and monkey STN neurons present a tonic activity with a
frequency varying from 5 to 65 Hz and few neurons discharge in bursts
(Matsumara et al. 1992
; Overton and Greenfield
1995
; Wichmann et al. 1994
). After the onset of
a conditioned movement, a period of high-frequency spikes is usually
recorded (Georgopoulos et al. 1983
; Matsumara et
al. 1992
; Miller and DeLong 1987
;
Wichmann et al. 1994
). In a pathological situation,
after a lesion of nigral dopaminergic neurons, there was an observed
increase in the percentage of bursts in the discharge of STN neurons in
rats and monkeys in vivo (Bergman et al. 1994
;
Hassani et al. 1996
; Hollerman and Grace
1992
) as well as in Parkinsonian patients (Benazzouz et
al. 1996
). We previously showed that approximately one-half of
the STN neurons recorded in slices in vitro have intrinsic membrane
properties that allow them to switch from a tonic to a burst-firing
mode in response to membrane hyperpolarization (Beurrier et al.
1999
).
This raises the question as to which conductances are altered by
afferent synaptic inputs to switch the activity of STN neurons from
single-spike to burst-firing mode (or the reverse). It is desirable to
first identify the set of ionic currents that are of demonstrable
importance in regulating the different firing modes. We previously
analyzed the cascade of currents underlying burst firing mode
(Beurrier et al. 1999). The aim of this study was to
build up a picture of the ionic mechanisms of the tonic firing mode
with the use of whole cell recordings of STN neurons in slices, in
current, or voltage-clamp mode. We analyzed the ionic currents
underlying the spontaneous depolarization that during the interspike
interval bring the membrane potential from the peak of the afterspike
hyperpolarization (AHP) to the threshold potential of
Na+ spike initiation. We now report that
pacemaker depolarization mainly results from the activation of a
subthreshold, slowly inactivating, TTX-sensitive
Na+ current
(INaP). We also show that in
approximately one-half of the neurons tested, the
hyperpolarization-activated cation current (Ih) blockade hyperpolarizes the
membrane sufficiently to switch STN activity to burst-firing mode, thus
suggesting that the fraction of Ih
opened at rest allows STN neurons to maintain a single-spike mode of activity.
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METHODS |
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Slice preparation
Experiments were performed on STN neurons in slices obtained
from 20- to 28-day-old male Wistar rats. Rats were anesthetized with
ether and decapitated. The brain was removed quickly and a block of
tissue containing the STN was isolated on ice in a 0-5°C oxygenated
solution containing (in mM) 1.15 NaH2PO4, 2 KCl, 26 NaHCO3, 7 MgCl2, 0.5 CaCl2, 11 glucose, and 250 saccharose, equilibrated with 95% O2-5%
CO2 (pH 7.4). This cold solution, with a low NaCl
and CaCl2 content, improved tissue viability. In
the same medium, 300- to 400-µm thick coronal slices were prepared using a vibratome (Campden Instruments, Loughborough, UK) and were
incubated at room temperature in a Krebs solution containing (in mM)
124 NaCl, 3.6 KCl, 1.25 HEPES, 26 NaHCO3, 1.3 MgCl2, 2.4 CaCl2, and 10 glucose, equilibrated with 95% O2-5%
CO2 (pH 7.4). After a 2-h recovery period, STN
slices were transferred one at a time to an interface-type recording
chamber, maintained at 30 ± 2 °C, and continuously superfused
(1-1.5 ml · min1) with the oxygenated
Krebs solution.
Electrophysiological recordings
Slices were viewed using a dissecting microscope and the
recording electrode was precisely positioned in the STN.
Electrophysiological recordings of STN neurons were performed in
current or in voltage-clamp mode using the blind patch-clamp technique
in the whole cell configuration. Patch electrodes were pulled from
filamented borosilicate thin-wall glass capillaries (GC150F-15, Clarck
Electromedical Instruments, Pangbourne, UK) with a vertical puller
(PP-830, Narishige, Japan) and had a resistance of 10 to 12 M when
filled with solution 1 (see Intracellular
solutions).
Intracellular solutions
For current-clamp recordings a K-gluconate-based solution
(solution 1) was used. It contained (in mM) 120 K-gluconate,
10 KCl, 10 NaCl, 10 EGTA, 10 HEPES, 1 CaCl2, 2 MgATP, and 0.5 NaGTP (pH 7.25). To study low-threshold
voltage-activated T-type Ca2+ current
(ICaT), the 120 mM K-gluconate in
solution 1 was substituted for an equimolar concentration of
CsCl and KCl was omitted as was ATP and GTP to reduce the L-type
Ca2+ current which is known to be sensitive to
run-down (solution 2). In some experiments the
Ca2+ chelator
1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetrapotassium salt (BAPTA, 10 mM) was added to solution 1 which contained 80 mM K-gluconate instead of 120 mM to obtain an
osmolarity ~270 mOsm · l1. In this
solution, the Ca2+ ion concentration was
decreased from 1 to 0.1 mM (solution 3). To record
Na+ currents, the 120 mM K-gluconate in solution
1 was substituted for an equimolar concentration of CsCl and KCl was
omitted (solution 4).
Extracellular solutions
For voltage-clamp experiments, the Krebs solution contained 1 µM TTX, 3 µM nifedipine, and 1 mM Cs+ for the ICaT study (solution A). For the INaP study, 2 mM Co2+ and 1 mM Cs+ were added and the Ca2+ ions concentration was decreased from 2.4 to 0.5 mM (solution B). For the Ih study, 1 µM TTX was added (solution C).
Drugs
All drugs were purchased from Sigma (St. Louis, MO), except
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX),
D-()-2-amino-5-phosphopentanoic acid (D-APV),
and bicuculline which were purchased from Tocris (Bristol, UK). BAPTA
was diluted in the pipette solution. All other drugs were diluted in
the oxygenated Krebs and applied through this superfusion medium.
Nifedipine and CNQX were dissolved in dimethylsulfoxide (final
concentration, 0.03-0.3%).
Data analysis
Membrane potential was recorded using an Axoclamp 2A or Axopatch
1D amplifier (Axon Instuments, Foster City, CA), displayed simultaneously on a storage oscilloscope and a four-channel chart recorder (Gould Instruments, Longjumeau, France), digitized (DR-890, NeuroData Instruments, NY), and stored on a videotape for subsequent offline analysis. In voltage-clamp experiments, membrane currents were
amplified by an Axopatch 1D or an Axoclamp 2A, fed into an A/D
converter (Digidata 1200, Axon Instuments), and stored and analyzed on
a PC using pCLAMP software (version 6.0.1, Axon Instruments). Because
different recording solutions were used throughout the study,
corrections for the liquid junction potential were performed. The
correction was 6 mV for the K-gluconate-based pipette solution as
estimated with a 3 M KCl ground electrode (Neher 1992
).
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RESULTS |
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Data presented here are based on patch-clamp recordings of 155 STN neurons. Neuronal activity was recorded in current-clamp mode (n = 57) and subthreshold currents were recorded in voltage-clamp mode (whole cell configuration, n = 106).
Characteristics of single-spike activity and pacemaker depolarization
All STN neurons displayed a single-spike mode of
Na+ action potentials (Fig.
1A) that was totally abolished
in the presence of 1 µM TTX. Action potentials had a mean threshold
of 42.2 ± 0.3 mV (range:
45 to
40 mV, n = 24) and were followed by an AHP that peaked at
57.1 ± 0.5 mV
(range:
54 to
62 mV, n = 25). Between consecutive
spikes, the membrane spontaneously depolarized by ~15 mV from the
peak of the AHP to the threshold potential of the following spike (Fig.
1B, control inset). By analogy with the pacemaker
activity of cardiac cells, we called this phase "pacemaker
depolarization" (DiFrancesco 1993
). The mean
frequency was 7.6 ± 0.8 Hz (range: 5.0-17.1 Hz,
n = 16) in the absence of current injection. When cells
were hyperpolarized by negative current injection, approximately
one-half of the recorded STN neurons shifted to burst-firing mode
(Beurrier et al. 1999
) with an AHP peaking at
61.8 ± 0.8 mV (range:
58 to
72 mV, n = 20) whereas the remaining one-half displayed single-spike mode but at lower
frequencies (Fig. 1A). At more hyperpolarized potentials both types of STN neurons were silent (Fig. 1A).
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Single-spike mode was not blocked by a concomitant application of CNQX,
D-APV, and bicuculline, the respective antagonists of
AMPA/kainate, NMDA, and GABAA ionotropic
receptors (Fig. 1B, n = 6), neither was it
suppressed by cobalt (Fig. 1C, Co2+ 2 mM, n = 32). These findings showed that the
TTX-sensitive, voltage-dependent single-spike activity is independent
of afferent synaptic activity (and particularly activation of
glutamatergic and GABAergic ionotropic receptors). This raised the
possibility that single-spike activity results from intrinsic
voltage-dependent properties of the membrane (i.e., from currents
underlying the pacemaker depolarization of the interspike interval that
spontaneously brings the membrane potential from the peak of the AHP to
the threshold potential for Na+-spike
initiation). During this phase, the net current is inward because a
decreasing outward current cannot by itself depolarize the membrane to
Na+-spike threshold (Irisawa et al.
1993). Moreover, inward currents are more efficient in
depolarizing the membrane whereas outward currents are decreasing and
membrane resistance is thus increased. More precisely, increase of
resistance depends on the density and deactivation characteristics
(kinetics and voltage dependence) of outward currents open at the peak
of the AHP. The subthreshold inward currents we analyzed were
ICaT,
Ca2+-activated inward (cationic) currents
(ICAN),
INaP, and
Ih. To identify which of these
currents was involved, we studied the effects of their pharmacological
blockade in current-clamp mode and analyzed their voltage dependence in
voltage-clamp mode. Does the membrane reach a level of depolarization
sufficient for this current to be activated during the interspike
interval? Does this current inactivate during repetitive firing?
ICaT
Nickel chloride at a concentration (Ni2+, 40 µM) that preferentially blocks T-type Ca2+
currents (Huguenard 1996) (Fig.
2B) did not affect
single-spike activity (Fig. 2A, n = 28) but
strongly reduced the rebound potential called low-threshold
Ca2+ spike (Nakanishi et al. 1987
)
seen at the break of a hyperpolarizing current pulse (Fig.
2A, insets). This is consistent with above observations that single-spike activity was still present under 2 mM
Co2+ (Fig. 1C). Voltage-clamp
experiments were performed in the presence of L-type
Ca2+ current blockers (see METHODS
solutions A and 2). Currents were evoked by step
depolarizations to varying test potentials from a holding potential of
80 mV. A low voltage-activated inward current that had the
characteristics of ICaT was recorded;
it activated at
59.3 ± 0.7 mV (range:
62 to
55 mV,
n = 10), presented a rather slow kinetic of
inactivation (Fig. 2B, left), and was totally
abolished in the presence of 40 µM Ni2+ (Fig.
2B, right). After a 7.5-s conditioning step at
59.9 ± 2.3 mV (range:
66 to
45 mV, n = 8),
it was fully inactivated (Fig. 2C). Because
ICaT is totally inactivated at
potentials crossed by the membrane during repetitive discharge, it is
unlikely that it participates significantly to the slow pacemaker
depolarization.
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Calcium-activated inward currents
BAPTA (10 mM), a Ca2+ chelator, was
introduced into the pipette solution (solution 3) to test
the participation of Ca2+-activated currents such
as ICAN, a current that is inward in the potential range of the pacemaker depolarization
(Crépel et al. 1994). In agreement with our
previous results (Beurrier et al. 1999
), BAPTA did not
affect single-spike mode (Fig. 3,
n = 5) although it effectively blocked
Ca2+-activated inward current as shown by the
strong reduction of the plateau potential duration evoked by a
depolarizing current pulse (Fig. 3, insets). This suggested
that Ca2+-activated currents are not absolutely
necessary to sustain single-spike activity. However, they may be
activated by a single spike and contribute to the pacemaker
depolarization.
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INaP
INaP is a TTX-sensitive
Na+ current that activates below spike threshold and slowly
inactivates (Crill 1996). The role of
INaP on the pattern of discharge in
current-clamp recordings is difficult to study because the
pharmacological subtances that block it (e.g., TTX or QX 314, a
derivative of lidocaine) are also blockers of the
Na+ spike. The role of
INaP in the pacemaker depolarization
was deduced from the analysis of its voltage dependence. Two protocols
were used, either a depolarizing ramp (Fig.
4A, speed 5 mV · s
1) or long depolarizing steps (1,500 ms) of increasing amplitude (Fig. 4B).
K+ currents were reduced by replacing
K+ ions by Cs+ in the
pipette solution (solution 4) and by adding 1 mM
Cs+ in the bath medium.
Ca2+ currents were suppressed by adding 2 mM
Co2+ in the bath medium and by decreasing the
external concentration of Ca2+ ions
(solution B). In response to the voltage ramp, an inward current that had the characteristics of a persistent
Na+ current
(INaP) was recorded; it activated at
54.4 ± 0.6 mV (range:
57.2 to
50.3 mV), peaked at
32.9 ± 0.8 mV (range:
37.4 to
26.8 mV), had a maximal
amplitude of
211.1 ± 8.5 pA (range:
266.1 to
164.2 pA), and
was totally abolished in the presence of 1 µM TTX (Fig.
4A, n = 13). Because
INaP peaked fast during the ramp
protocol, probably because it came out of voltage control and because
INaP can partially inactivate during
the time course of the ramp command, the voltage step protocol was also
tested. From a holding potential of
80 mV, a slowly inactivating
Na+ current was observed (Fig. 4B). It
activated from
56.9 ± 1.3 mV (range:
60 to
50 mV,
n = 10) and was totally abolished in the presence of 1 µM TTX (Fig. 4, B and C).
INaP inactivated slowly (~20%)
during a 5-s voltage step at
42 mV
(VH =
60 mV, n = 5, data not shown). Voltage-dependent steady-state inactivation was studied with the protocol shown in Fig. 4D. After 5 s
at approximately
50 mV (n = 13),
INaP was one-half inactivated and
after 5 s at
30 mV was fully inactivated (Fig. 4, D
and E). To approach the situation during regular spiking,
another protocol was tested. A situation where the membrane was rather
depolarized was chosen; from a holding potential of
50 mV (to mimick
the AHP), a 1-ms step to +20 mV was applied (to mimic a spike) and was
followed by a 5-s step to
35 mV (to evoke
INaP and measure channel
availability). The two steps were separated by an interval of variable
duration (15-60 ms) at
50 mV (to mimic the interspike interval)
(Fig. 5, left). It was
noteworthy that INaP was not
inactivated by the first depolarizing pulse but also that it had a
larger amplitude at shorter intervals. Further increases in interval
duration gave a stable 30% reduction of
INaP (Fig. 5, right). In
conclusion, INaP activates in a
potential range crossed by the membrane during the interspike interval
and is not totally inactivated after a spike.
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Ih
The cesium-sensitive cation current
Ih is turned on by membrane
hyperpolarization and is inward (depolarizing) at potentials more
hyperpolarized than its reversal potential (approximately 30 mV)
(Pape 1996
). In ~50% of the neurons tested
(n = 5 of 11), adding cesium chloride
(Cs+, 1-3 mM) to external Krebs solution
hyperpolarized the membrane by approximately
12 mV and switched their
activity from tonic-firing to burst-firing mode (Fig.
6A). When positive current was
injected, tonic activity reappeared though
Ih was still blocked (Fig.
6A, bottom right and inset). In the remaining
one-half of the cells, Cs+ did not affect
membrane potential or tonic activity (n = 6).
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Characteristics of Ih were
studied in current-clamp and voltage-clamp modes (solutions
C and 1). In response to long hyperpolarizing currents
pulses (500 ms), a time-dependent,
Cs+-sensitive anomalous rectification, seen as a
slowly developing depolarizing sag, was observed (Fig. 6A,
insets). This sag corresponded in voltage-clamp recordings to a
slowly developing inward current that activated at 56.5 ± 0.8 mV (range:
60 to
55 mV, n = 10) in response to
hyperpolarizing steps from a holding potential of
45 mV and increased
in amplitude with membrane hyperpolarization (Fig. 6, B and
C). This current was strongly depressed in the presence of 1 to 3 mM external Cs+ (Fig. 6, B and
C). From the above results we conclude that
Ih is not essential for a tonic mode
of discharge. However, in some cells it contributes toward
maintaining membrane potential at a more depolarized value where
tonic mode is present.
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DISCUSSION |
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These results show that single-spike activity of STN neurons is independent of afferent synaptic activity and of Ca2+ or Ca2+-activated currents. It mainly results from the persistent Na+ current, INaP. Moreover, in some neurons a sustained fraction of Ih exerts a depolarizing influence, enables the membrane potential to reach the threshold for INaP activation and thus favors the single-spike mode of discharge. The role of INaP in STN neurons has been deduced from its voltage-dependent characteristics whereas that of Ih was also deduced from the effect of its blockade by external Cs+.
INaP underlies the pacemaker depolarization in the single-spike mode
We propose that the pacemaker depolarization that precedes each action potential is mainly mediated by the slowly inactivating Na+ current, INaP. Single-spike mode is voltage-dependent and both action potentials and pacemaker depolarizations were abolished by TTX, a specific blocker of voltage-sensitive Na+ currents whereas they were insensitive to blockers of Ca2+ currents. These observations can be linked to voltage-clamp experiments where a TTX-sensitive inward current recorded in all STN neurons tested, activated at voltages clearly below spike threshold and normally traversed by spontaneously firing cells. This current represented INaP because there was no residual current in the presence of TTX and a contribution of Ca2+ currents is most unlikely in the presence of cobalt and very low concentrations of Ca2+ in the extracellular medium. Interestingly, nonbursting STN neurons were silent at voltages more hyperpolarized than the INaP threshold of activation. However, insights into the functional relevance of INaP for single-spike activity need also to consider its inactivation properties. INaP could still be evoked a few milliseconds after a short depolarization that mimicked a spike.
Comparison with other preparations where
INaP plays also a role in spontaneous
tonic firing showed that the voltage range of
INaP activation threshold in our
experiments is ~5-10 mV more positive than that found in other
central neurons such as neocortical layer V pyramidal neurons
(Stafstrom et al. 1985), medial entorhinal neurons
(Alonso and Llinas 1989
), suprachiasmatic neurons
(Pennartz et al. 1997
), Purkinje cells (Llinas
and Sugimori 1980
), and hippocampal neurons (French et
al. 1990
; MacVicar 1985
).
ICaT recorded in this study does not
play a significant role in single-spike mode because it is inactivated
at potentials where STN neurons fire tonically. Kinetic of inactivation
of ICaT recorded in this study is
close to that described for a T current mediated by the recently cloned
1l subunit (Lee et al. 1999
), which transcript is
highly expresssed in the STN (Talley et al. 1999
).
Role of a sustained Ih component
We suggest that a sustained component of the
Cs+-sensitive
Ih, open at resting membrane
potential, contributes toward maintaining single-spike firing in some
STN neurons. This is important because the value of membrane potential
critically determines the pattern of firing of STN neurons
(Beurrier et al. 1999). Cs+
produced a hyperpolarization that was large enough to move the cell
into the burst mode of action potential generation. This was only
observed for cells that displayed a plateau potential in control
conditions. We have certainly underestimated
Ih amplitude and the effects of its
blockade with the use of gluconate ions in the pipette solution.
Gluconate ions give more physiological recordings but are known to
inhibit Ih (Velumian et al.
1997
). Moreover, it could also be argued that external
Cs+ also affects delayed and inward rectifier
K+ currents. However, because these currents are
outward, their blockade will result in membrane depolarization instead
of hyperpolarization. We can hypothesize that a sustained component of
Ih as a result of its depolarizing
influence moves the membrane potential from a range of
Ca2+-mediated burst activity into a region where
it activates INaP and allows a
single-spike mode of discharge. Such a contribution of
Ih to resting parameters has already
been described in thalamic relay neurons, cells that also display two
intrinsic modes of discharge depending on membrane potential
(McCormick and Pape 1990
; Pape 1996
). For
the fraction of Ih that is activated
on hyperpolarization and deactivated with depolarization, most of its
depolarizing effect would be efficient at hyperpolarized potentials when STN neurons are discharging in the bursting mode. One remarkable feature of Ih channels is the presence
of a cyclic nucleotide binding region that allows
Ih to be modulated by second
messengers. Cyclic AMP or cyclic GMP increase
Ih channels activities by shifting their activation curve to more depolarized values (Ludwig et al. 1999
; Santoro et al. 1998
). The modulation of
the voltage dependence of Ih through
the production of cAMP would thus have important consequences on the
firing pattern of STN neurons.
We propose that STN activity shifts from burst-firing mode to
single-spike activity in response to a depolarization which induces
inactivation of the calcium conductances such as
ICaT (which cannot generate any more
slow membrane oscillations) and activation of the subthreshold
depolarizing currents Ih and
INaP. Conversely, tonic-firing mode
would cease once the membrane is more hyperpolarized than the
INaP threshold of activation.
Therefore the increase in the percentage of bursts recorded in the STN
after the experimental lesion of nigral dopaminergic neurons
(Bergman et al. 1994; Hassani et al.
1996
; Hollerman and Grace 1992
) or in the
absence of dopaminergic neurons (Plenz and Kitai 1999
) would result from a synaptically driven hyperpolarizing shift of the
background resting potential of STN neurons.
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ACKNOWLEDGMENTS |
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Present address of C. Beurrier: Stanford University, School of Medicine, Dept. of Psychiatry and Behavioral Sciences, 1201 Welch Rd., Palo Alto, CA 94304-5485.
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FOOTNOTES |
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Address for reprint requests: C. Hammond, INSERM U29, INMED, Route de Luminy, BP13, 13273 Marseille Cedex 09, France.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 20 September 1999; accepted in final form 29 November 1999.
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NOTE ADDED IN PROOF |
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Since this paper was submitted for publication, a report by Bevan et al. was published (J. Neurosci. 19: 7617-7628, 1999) showing also that INaP plays a role in the tonic mode of discharge of STN neurons. However, the contribution of Ih has not been studied by the authors.
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REFERENCES |
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