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Vol. 284, Issue 1, 228-237, 1998
Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington 98195-7290
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Abstract |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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We examined the effect of the anticonvulsant phenytoin (PT) (20-200 µM) on the persistent Na+ current (INaP), INaP-dependent membrane potential responses and repetitive firing in layer 5 pyramidal neurons in a slice preparation of rat sensorimotor cortex. INaP measured directly with voltage-clamp was reduced in a concentration-dependent manner with an apparent EC50 value of 78 µM. Clear effects on current-evoked membrane potential responses were apparent at 50 µM PT: Subthreshold, depolarizing membrane potential rectification was reduced, rheobase current was increased and the relation between firing rate and injected current was shifted to the right, but action potential amplitude and duration were unaffected. We ascribed these effects of PT largely to the reduction of INaP. A slow decline of firing rate during the injected current pulse also became apparent at moderate PT concentrations. When PT concentration was raised to 150 to 200 µM, this slow adaption was enhanced markedly, and firing ceased during a sufficiently large current pulse. This enhanced slow adaptation and the cessation of firing were associated with a marked decline of spike amplitude and a rise in spike firing level during successive interspike intervals. We ascribe these effects largely to the action of PT on the transient Na+ current. We conclude that the reduction in cortical neuronal excitability by PT depends partly on its reduction of INaP, the effects of INaP blockade are apparent at PT concentrations lower than those required to abolish tonic firing and the cells need not be excessively depolarized for PT to decrease excitability by its effect on INaP.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The
anticonvulsant PT is widely used to control generalized and partial
seizures (Rogawski and Porter, 1990
; Woodbury, 1980). A variety of
cellular effects have been observed when PT was applied to different
preparations (Rogawski and Porter, 1990; Woodbury, 1980), but the
therapeutic effects of PT are thought to derive mainly from its
blockade of voltage-gated Na+ channels (MacDonald
and Kelley, 1993; MacDonald and McLean, 1986; Rogawski and Porter,
1990). Studies on the fast INa indicate that PT
binds tightly but slowly to block the Na+
channels in both their open and their inactivated states, whereas PT
binds only weakly to the closed ("resting") channel (Kuo and Bean,
1994; Ragsdale et al., 1991; Willow et al.,
1985). The binding of PT to open Na+ channel
results in a use-dependent block of INa during
brief, repetitive depolarizations (Ragsdale et al., 1991;
Schwartz and Grigat, 1989; Willow et al., 1985). The binding
of PT to the inactivated channel results in a voltage-dependent
blockade of INa (Kuo and Bean, 1994; Ragsdale
et al., 1985; Schwartz and Grigat, 1989; Willow et
al., 1985). During a long-lasting depolarization,
INa is activated only briefly before becoming
inactivated. Thus, binding of PT to the inactivated
Na+ channel has been considered the important
practical binding mode for PT action on Na+
channels.
The properties of PT binding outlined above have led to the idea that
PT will preferentially bind to and block Na+
channels in neurons that are depolarized tonically and firing action
potentials at a high rate. Less effect would be expected on neurons
engaged in slow-rate firing because the time-average value of
Na+ inactivation (and, therefore, PT binding and
INa blockade) is expected to be lower when action
potentials are less frequent. Support for this idea has been provided
by MacDonald and McLean (1986) and McLean and MacDonald (1983) in
experiments on cultured murine neurons. In these experiments,
long-lasting, depolarizing, injected current pulses evoked only a few
initial action potentials, followed by a cessation of firing in the
presence of PT, whereas the same pulses evoked tonic, high-rate firing
in control solution.
Many neurons possess a second type of Na+
current, a "persistent," or slowly inactivating,
Na+ current (INaP) (Taylor
1993) that is activated at membrane potentials negative to spike
threshold (Stafstrom et al., 1982, 1985). Although it is a
relatively small current, INaP is an important
determinant of excitability near spike threshold because it is largely
unopposed by other voltage-gated currents in this subthreshold range of membrane potentials. There is evidence that INaP
in cortical pyramidal neurons flows through a fraction of the same
Na+ channels that normally give rise to the
transient Na+ current but temporarily fail to
inactivate for an extended period of time (Alzheimer et al.,
1993). This fraction of open Na+ channels would
be expected to be susceptible to the open-channel binding of PT, and it
has been shown recently that INaP measured in
acutely dissociated mammalian central neurons is inhibited by PT in a
concentration-dependent manner (Chao and Alzheimer, 1995).
We hypothesized that PT may reduce neuronal excitability by its
inhibition of INaP in addition to its well known
action on INa. It seemed possible that by its
action on INaP, PT may reduce excitability at a
lower concentration than needed to block high-rate repetitive firing.
Furthermore, the large depolarizations that result in inactivation of
INa should not be required for PT to affect
INaP because PT can bind to the open
Na+ channels that give rise to
INaP during small depolarizations. To investigate
this question, we examined the action of PT on INaP and INaP-dependent
membrane potential responses in layer 5 pyramidal neurons in a slice
preparation of rat sensorimotor cortex. Although PT has already been
shown to reduce INaP in dissociated cortical
neurons (Chao and Alzheimer, 1995), the consequences of
INaP reduction on cell excitability have not been
examined. The effect of PT on repetitive firing has been examined only
in cultured murine neurons bathed in a low Ca++
solution (McLean and MacDonald, 1983). Therefore, we also examined the
effect of PT on repetitive firing of the layer 5 pyramidal cells to
compare, in the same preparation and conditions, the PT concentrations
that affected repetitive firing with the concentrations that affected
subthreshold, INaP-dependent membrane potential responses and INaP measured directly by
voltage-clamp.
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Sprague-Dawley rats (28-35 days postnatal) were anesthetized
with ketamine (150 mg/kg) and xylazine (10 mg/kg) and killed by carotid
section. A coronal section of cortex 0 to 3 mm posterior to bregma was
isolated, and slices 350 µm thick were prepared and maintained as
described previously (Schwindt and Crill, 1995). Recorded cells lay 1.0 to 1.3 mm below the pial surface and 2.1 to 3.2 mm from midline,
corresponding to layer 5 of areas HL and FL of sensorimotor cortex
(Zilles and Wree, 1985).
Intracellular recordings were made with the slice submerged in a
chamber of 
0.25 ml volume maintained at 33° to 34°C and perfused
at 1 to 2 ml/min. Slices were perfused with physiological saline
consisting of (in mM) 130 NaCl, 3 KCl, 2 CaCl2, 2 MgCl2, 1.25 NaH2PO4 and 10 dextrose
saturated with 95% O2/5%
CO2, pH 7.4. PT (Sigma Chemical, St. Louis, MO)
was prepared as a 100 mM stock solution in DMSO. Aliquots of this stock
were added to the perfusate just before intracellular recording to
attain final PT concentrations up to 200 µM. Control experiments
(n = 3) were performed using the maximal DMSO
concentrations (0.1-0.2%) to ensure that the reported effects were
not caused by DMSO.
Cells were impaled with sharp microelectrodes made from standard 1.0-mm
outer diameter borosilicate tubing and filled with 2.7 M KCl (DC
resistance, 30-40 M
). An Axoclamp-2A amplifier (Axon Instruments,
Foster City, CA) was used to record membrane potential and inject
current in active bridge mode or discontinuous current clamp mode or to
control somatic membrane potential in single-electrode voltage-clamp
using a switching rate of 2.5 to 5.5 kHz (30% duty cycle). Membrane
potential and injected current were monitored and filtered at 1 to 10 kHz; membrane current measured in voltage-clamp was filtered at 100 Hz.
Signals were amplified and recorded on a multichannel videocassette
recorder with pulse code modulation (Neuro-Data, New York, NY;
two-channel sampling rate, 44 KHz). Resting potential was taken as the
difference between the intracellular and extracellular potentials
recorded on a chart recorder. Recorded data were digitized to analyze
evoked responses and firing rates using a computer program.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Intracellular recordings were obtained from 26 neurons. The
recording microelectrode was placed at a depth below the pial surface
to record from layer 5 (see Methods). All recorded neurons had
relatively low input resistance (see below), and all exhibited current-evoked repetitive firing responses (burst firing or regular spiking) characteristic of pyramidal neurons (McCormick et
al., 1985). Neurons used for this study had a stable resting
potential negative to 
60 mV and did not fire spontaneously.
Resting potential and input resistance.
The effects of PT on
both resting potential and input resistance were examined
quantitatively in 11 neurons. PT (25-150 µM) had no effect on
resting potential (control, 71.9 ± 5.3 mV; PT, 71.6 ± 5.8 mV; P > .6, paired t test, n = 11). In the same neurons, the voltage responses at the end of a series
of 1-sec negative current steps were measured and plotted as function
of injected current (data not shown). The slope of a linear fit to this
plot (between 0 and 0.5 nA) was taken as input resistance. No
significant change of input resistance was found after the application
of PT (control, 16.4 ± 4.7 M; PT, 17.5 ± 5.5 M;
P > .2, paired t test, n = 11; also
see voltage-clamp results below).
Alteration of repetitive firing. Measurements of repetitive firing properties and their alteration by PT were made in the same 11 neurons described above. Repetitive firing was evoked by 1-sec current steps of increasing amplitude before and after the addition of PT (25-100 µM). Most data were obtained using 50 µM PT. Two aspects of the repetitive response were altered by PT: The firing evoked throughout most of a given current pulse was significantly slower than in control, and a slow decline of firing rate during the pulse became apparent after PT application. Typical results are illustrated in figure 1. Figure 1, A-D, shows how the firing evoked by a current pulse was altered by PT (50 µM). The slower firing rate evoked by this pulse in PT is seen most clearly in figure 1, C and D, which shows the last 600 msec of the response of figure 1, A and B, at a faster time scale. The plots of figure 1, E and F, show instantaneous firing frequency (1/interspike interval) as a function of action potential number during current pulses. The three different curves in each plot correspond to the responses evoked by three different currents. By comparison of the control curves (fig. 1E) with those obtained after application of PT (fig. 1F), it can be seen that firing rate was slower than control even during the first interspike interval at the smallest current pulse (bottom plot) and was slower than control starting from the second interspike interval during the two larger pulses (top two plots). Among the 11 cells examined, PT had no consistent effect on instantaneous firing rate during the first interspike interval (off scale in the plots of fig. 1, E and F) or sometimes during the second interspike interval, when the instantaneous rate during these early intervals (evoked by larger current pulses) was >50 to 100 Hz.
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) was slower than the control (fig. 2A, 
). This effect of PT
was reversible (fig. 2A) and concentration dependent (fig. 2B). The
average firing rates obtained after application of PT had a larger
variance than in control (see error bars in fig. 2, A and B), but this
larger variance resulted from a slow decline of firing rate throughout
the current pulse rather than from large fluctuations in the interspike
interval (see below). The slope of the F-I relations were measured by
fitting a line to the data points between 0 and 0.8 nA (dotted lines in
fig. 2). Despite the lower average firing rates obtained in PT, the F-I
slopes were essentially unchanged (control slope, 34.2 ± 9.7 Hz/nA; PT slope, 33.4 ± 8.1 Hz/nA, P > .3, paired
t test, n = 11).
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30% more than control was needed to initiate steady firing in the
presence of PT.
Figure 1, C and D, also illustrates our second finding that a slow
decline of firing rate (slow spike frequency adaptation) first appeared
or became more prominent in the presence of PT. In the control record
(fig. 1C), interspike interval duration remained essentially constant
during the last 600 msec of the current pulse, whereas the interspike
intervals lengthened progressively in the presence of PT (fig. 1D). The
effect of PT (50-100 µM) on slow spike frequency adaptation was
examined quantitatively in 4 neurons. For each cell, we fit the
adaptation relation from the seventh to the last action potential by a
line, as shown in figure 1, E and F. In each cell, the slopes of these
lines were independent of injected current strength (P > .2, one-way ANOVA). We calculated the average slope of the line in control
solution and after PT application. In the presence of PT, firing rate
declined 4 times faster than the control (control, 0.035 ± 0.049 Hz/spike; PT, 0.144 ± 0.046 Hz/spike, n = 4).
A higher concentration of PT greatly enhanced this slow decline of
firing rate, as illustrated in figure 3.
When 200 µM PT was applied to this cell, firing rate declined to zero
during injection of a sufficiently large current pulse (fig. 3B, top trace). The neuron did not stop firing during the injection of smaller
currents (fig. 3B, bottom trace), but the slow decline of firing rate
was much greater than at lower PT concentrations (compare fig. 3B,
bottom trace, with fig. 1B). The amplitude of successive action
potentials also decreased markedly after PT application in figure 3,
whereas they were unaltered at lower PT concentrations (compare fig.
3B, bottom trace, with fig. 1B). Both the progressive decline of
successive action potentials (at all currents tested) and the cessation
of firing (during larger current pulses that evoked tonic firing in
control) were observed in each of 4 cells tested when PT concentration
was raised to 150 µM (n = 1) or 200 µM
(n = 3).
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Alteration of spike threshold and rheobase current. The effect of PT on spike threshold was investigated further by evoking single spikes with briefer current pulses. In figure 5A, the firing level of a single spike, evoked by 100-msec current pulse, was increased by 2.5 mV after the addition of 100 µM PT. Superimposition of the action potentials obtained in each solution (fig. 5B) shows that this concentration of PT had no significant effect on spike amplitude or duration. (The control spike appears be slightly larger in figure 5B because spike threshold was the reference point used for the superposition.) In 4 other cells tested similarly, we found no significant change in the duration or amplitude of single action potentials evoked in the presence of PT concentrations that caused the changes in firing level and repetitive firing described above.
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, 1985). Indeed, the depolarizing rectification observed in this
cell after washout of PT was blocked by the subsequent application of
TTX (data not shown).
Alteration of persistent Na+ current.
Experiments were conducted on 17 cells to confirm by direct measurement
that PT reduced INaP and to determine the
effective PT concentrations for comparison with concentrations that
affected the near-threshold membrane potential responses and repetitive firing. INaP was recorded in voltage clamp (see
Methods) using a voltage command consisting of a slow (1-3-sec
duration) ramp depolarization from resting potential. This
depolarization is slow enough to inactivate INa
and reveal INaP (Alzheimer et al., 1993; Stafstrom et al., 1982, 1985). A typical voltage-clamp
response is illustrated in figure 6A. In
this figure, the control membrane current evoked by the depolarizing
ramp voltage clamp is superimposed on the membrane current measured
after application of 50 µM PT and on the current measured after
partial washout of PT. Inward rectification is apparent on the control
record as the cell is depolarized. PT reduced this inward
rectification, and some recovery was observed after 10 min of washout.
When membrane potential reached 52 mV, an uncontrolled action current
was evoked, as can be seen on both the voltage and current records of
all three traces. Because the single-electrode voltage-clamp cannot
control the large, fast, inward current associated with an action
potential, the ramp depolarization was terminated when somatic membrane
potential reached firing level. This limited the depolarization to
50 mV among the cells tested.
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, 1985; see fig.
7A). INaP was first
activated at 65 mV in the cell of figure 6. PT reduced the inward
rectification (i.e., INaP) reversibly,
but the leakage conductance was unaffected. The effect of PT on the
inward rectification was concentration dependent, as illustrated for
another cell in figure 6C. The blockade of INaP
in this cell was not quite complete even at 200 µM PT.
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60 mV)
were fit adequately by a horizontal line. This procedure revealed a
concentration-dependent reduction of GNaP by PT
(fig. 7C).
In each of these 17 cells, we examined the effect of one to three
concentrations of PT in the range of 20 to 200 µM. In these cells,
the initial, linear portion of the I-V curve did not change significantly after application of PT (P > .4, paired
t test), supporting our finding that input conductance
measured in current-clamp was not affected significantly by PT. The
average relative GNaP in each cell was based on
the I-V relations for INaP between 60 mV and
55 mV. A voltage-dependent reduction of GNaP
was not detected by this procedure, possibly because the reduction was
only examined over a 5- to 10-mV range of membrane potential. Values
from the 17 cells were pooled and plotted as a function of PT
concentration after averaging across cells (fig.
8, triangles). The error bars in this
plot indicate considerable variability of GNaP
reduction at a given PT concentration among the cells tested, a point
that also is made by the disparate concentration-response relations shown for 2 individual cells (fig. 8, filled symbols). This variability in PT effectiveness may reflect the existence of cells that differ in
their sensitivity to PT. It also could reflect variability in the
actual PT concentration attained at the cell membrane in a slice
preparation, as mentioned in the Discussion. A fit to this
concentration-response curve on the assumption of first-order drug-receptor binding (Kuo and Bean, 1994) resulted in an
EC50 value of 78 µM.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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We found that PT affected INaP,
INaP-dependent membrane potential responses and
repetitive firing properties in a graded, concentration-dependent
manner. The clearest relation between the reduction of
INaP and the reduction of excitability was the reduction of the subthreshold, depolarizing rectification that causes
membrane potential to rise to firing level (arrow in fig. 5C), which is
well documented to depend on INaP activation
(Stafstrom et al., 1982, 1985). The failure of membrane
potential to reach firing level during injection of a control current
pulse necessitated the use of a larger (rheobase) pulse to evoke a
spike. Because a larger current was needed to evoke a single spike in
the presence of PT, we would expect a larger current also to be needed
to evoke steady repetitive firing, as was observed. The requirement for a larger current to evoke repetitive firing in the presence of PT would
naturally cause the F-I relation to shift to the right, and we may
confidently ascribe part of this rightward shift to the reduction of
INaP. INaP is active at
membrane potentials traversed in the interspike interval during
repetitive firing (Stafstrom et al., 1984). Reduction of
INaP would therefore delay the rise of membrane
potential to firing level during repetitive firing, resulting in a
longer interspike interval and slower firing rate. This is a second way
by which the reduction of INaP would contribute to the rightward shift of the F-I curve. These effects were observed with no change in spike amplitude or duration. Therefore, we ascribe these effects principally to the reduction of
INaP by low to moderate concentrations of PT. The
alteration of these INaP-dependent factors would
reduce the excitability of all cells, not just those that are
excessively depolarized. Indeed, we observed reduced excitability at
rheobase current and at the minimum steady firing rate.
We would expect the reduction of INaP to depend
at least partly on the binding of PT to open Na+
channels, but our data shed no light on this. At the usual resting potentials encountered in the slice preparation (70 mV),
INa is expected to be partly inactivated (Brown
et al., 1994; Huguenard et al., 1988). The
binding of PT to inactivated channels that might otherwise have
returned to the resting state, and even the much weaker binding of PT
to channels in the resting state would reduce the total number of
Na+ channels available to open during
depolarization, including channels that might otherwise have
contributed to INaP generation. This mechanism
may reduce INaP as effectively as open-channel
binding and blockade. One might expect to observe the same type of
voltage-dependent block of INaP that is seen for
INa. The necessity of evoking an INaP that was sufficiently large to measure
accurately at membrane potentials below spike threshold limited our
observation to a voltage range (5-10 mV) that was too small to detect
a clear voltage dependence of INaP reduction. It
should be realized that our methods and preparation were directed
toward measuring changes in excitability rather than questions of
channel biophysics.
The alteration of repetitive firing was finely graded by PT
concentration in our experiments; this allowed us to gain some insight
into the factors that result ultimately in the cessation of repetitive
firing when PT concentration reached a critical level. PT caused a
concentration-dependent increase in slow spike frequency adaptation
that was associated with a progressive rise in firing level from
interval to interval. Because spike threshold depends on the balance of
inward and outward currents and INaP causes a
net-inward current to develop in some cells (Stafstrom et
al., 1982, 1985), it is possible that the reduction of
INaP also contributed to the rise of firing level
at moderate PT concentrations at which spike amplitude was unaffected.
At high concentrations of PT, the conclusion seems inescapable that the
marked rise in firing level and decrease in spike amplitude during the
repetitive firing were caused primarily by the progressive reduction of
INa as a consequence of the slow binding of PT to
inactivated Na+ channels (Kuo and Bean, 1994).
The progressive decline of spike amplitude is likely to hasten further
the inactivation and blockade of Na+ current.
Less-repolarizing K+ current would be activated
by a smaller spike, membrane potential during the next interspike
interval would become more depolarized (see fig. 3B) and steady-state
Na+ inactivation (thus, PT binding) would
increase. Thus, we ascribe the rapid decline of firing rate (ultimately
to zero) seen at high PT concentrations largely to the reduction of
INa by PT.
Our repetitive firing results are consistent in two respects with those
of McLean and MacDonald (1983) on cultured murine neurons: We confirmed
that PT ultimately can cause the cessation of repetitive firing during
a long-lasting depolarization, and the repetitive firing ceased sooner
when the initial firing rate was faster. Our results differ in other
respects, however. McLean and MacDonald (1983) interpreted their
results as indicating that PT preferentially binds to and blocks
Na+ channels in neurons that are firing action
potentials at a high rate while having little or no effect on those
neurons engaged in slow-rate firing. Although we found that PT could
block high-rate firing, we found that firing at all rates was slowed by
PT. Therefore, the effects of PT appear to be less selective for
high-rate firing than previously thought.
A second major difference in our results is the PT concentration that
resulted in a cessation of firing. McLean and MacDonald (1983) found
this to occur at PT concentrations of 4 to 8 µM, whereas firing
ceased at concentrations of 150 to 200 µM in our experiments. This
discrepancy may be explained by factors that differed in the two sets
of experiments. The average resting potential of the murine neurons was
10 mV more depolarized than in this study. To eliminate synaptic
potentials, McLean and MacDonald (1983) recorded in a
low-Ca++, high-Mg++
solution, which was also likely to reduce or block the
Ca++-dependent K+ currents
that are primarily responsible for repolarizing membrane potential
during the interspike interval. The EC50 for
INa blockade may decrease 100 fold as a neuron
is depolarized (Kuo and Bean, 1994). Because of this remarkable
dependence of EC50 on membrane potential,
differences in resting potential, firing level and membrane potential
during the interspike interval could significantly alter the effective
concentration at which PT causes firing to cease.
It also is possible that the actual PT concentration at our recorded
cells was considerably less than the nominal bath concentration because
we recorded in a slice. PT is highly lipophyllic and binds to a variety
of proteins (Goldberg, 1980). Our recorded cells invariably were near
the center of the slice, and data were collected within 20 min after
the solution change to ensure the observed effects were not due to cell
deterioration during a long impalement and to allow time for PT washout
without excessive cell deterioration. It is possible that the binding
of PT to elements in overlying tissue caused the PT concentration at
the recorded cell to remain below the nominal bath concentration during
the time frame of our recording. Some indication that this might be the
case is given by our apparent EC50 value for the
reduction of INaP (fig. 8); it was 2.5 times
greater than that reported by Chao and Alzheimer (1995) for the
reduction of INaP in the same type of cells. A possible reason for this discrepancy is that the membrane of the dissociated cells experienced the bath PT concentration, whereas ours
did not. Although the use of dissociated cells in the present study
would have eliminated this problem, we chose to study the effect of PT
on cells with normal structure (e.g., dendrites) and
intracellular milieu and at a more physiological temperature, conditions that are difficult to meet using the dissociated cells.
The slow, voltage-dependent binding kinetics of PT makes it difficult to adequately assess the effectiveness of PT in reducing repetitive firing by the use of a 1-sec depolarization. Because we found that the slowing of firing rate continued throughout a 1-sec depolarizing pulse at moderate PT concentrations (e.g., 50 µM), it is possible that firing rate ultimately would have declined to zero had the depolarization been prolonged indefinitely. Our results show, however, that other manifestations of decreased excitability, such as the rightward shift of the F-I relation and raised rheobase current, result from the reduction of INaP as well as INa.
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Acknowledgments |
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We thank Gregg Hinz and Paul Newman for excellent technical assistance.
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Footnotes |
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Accepted for publication September 25, 1997.
Received for publication May 22, 1997.
1 This work was supported by International Human Frontiers Science Program Grant LT-544/94 (I.L.) and National Institutes of Health Grant NS16792 and the Keck Foundation (P.C.S. and W.E.C.).
Send reprint requests to: Dr. P. C. Schwindt, Department of Physiology and Biophysics, University of Washington School of Medicine, Box 357290, Seattle, WA 98195-7290. E-mail: schwindt{at}u.washington.edu
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Abbreviations |
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PT, phenytoin sodium; TTX, tetrodotoxin; INaP, persistent sodium current; GNaP, persistent sodium current conductance; INa, transient sodium current; EC50, concentration causing half-inhibition; ANOVA, analysis of variance; DMSO, dimethylsulfoxide; I-V, current-voltage.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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