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Volume 17, Number 17,
Issue of September 1, 1997
pp. 6512-6521
Copyright ©1997 Society for Neuroscience
Slow Recovery from Inactivation of Na+ Channels
Underlies the Activity-Dependent Attenuation of Dendritic Action
Potentials in Hippocampal CA1 Pyramidal Neurons
Costa M. Colbert,
Jeffrey C. Magee,
Dax A. Hoffman, and
Daniel Johnston
Division of Neuroscience, Baylor College of Medicine, Houston,
Texas 77030
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Na+ action potentials propagate into the
dendrites of pyramidal neurons driving an influx of
Ca2+ that seems to be important for associative
synaptic plasticity. During repetitive (10-50 Hz) firing, dendritic
action potentials display a marked and prolonged voltage-dependent
decrease in amplitude. Such a decrease is not apparent in somatic
action potentials. We investigated the mechanisms of the different
activity dependence of somatic and dendritic action potentials in CA1
pyramidal neurons of adult rats using whole-cell and cell-attached
patch-clamp methods. There were three main findings. First, dendritic
Na+ currents decreased in amplitude when repeatedly
activated by brief (2 msec) depolarizations. Recovery was slow and
voltage-dependent. Second, Na+ currents decreased
much less in somatic than in dendritic patches. Third, although
K+ currents remained constant during trains,
K+ currents were necessary for dendritic action
potential amplitude to decrease in whole-cell experiments. These
results suggest that regional differences in Na+ and
K+ channels determine the differences in the
activity dependence of somatic and dendritic action potential
amplitudes.
Key words:
potassium channels;
modulation;
whole-cell;
cell-attached;
electrophysiology;
rat
INTRODUCTION
Pyramidal neurons often initiate
action potentials in the axosomatic region (Turner et al., 1991 ; Stuart
and Sakmann, 1994; Spruston et al., 1995; Colbert and Johnston, 1996b).
Once the action potential fires, it propagates not only along the axon but also "backward" throughout much of the dendritic arbor (Turner et al., 1991; Spruston et al., 1995). These backpropagating dendritic action potentials are primarily mediated by Na+ ions
but drive an influx of Ca2+ ions that may provide a
sufficient postsynaptic signal for associative synaptic plasticity
(Jaffe et al., 1992; Markram and Tsodyks, 1996; Magee and Johnston,
1997). Unlike somatic action potentials, which remain relatively
constant in amplitude, dendritic action potentials display an
activity-dependent decrease in amplitude that is voltage-dependent and
slow in its recovery (Callaway and Ross, 1995; Spruston et al., 1995;
Tsubokawa and Ross, 1996a). These decreases in amplitude are
accompanied by reduced Ca2+ influx (Callaway and
Ross, 1995; Spruston et al., 1995) and are, therefore, likely to
determine some of the time- and activity-dependent properties of
synaptic plasticity. The mechanism of the decrease in dendritic action
potential amplitude, however, is not known. A number of candidate
mechanisms have been considered in the theoretical literature
(Migliore, 1996).
The present study was aimed at identifying properties of voltage-gated
ion channels that might underlie the activity-dependent decrease in
dendritic action potential amplitude. We hypothesized that repetitive
activation of voltage-gated channels, as would occur during a train of
dendritic action potentials, might alter channel properties. Using
cell-attached patch-clamp techniques, we observed isolated currents in
patches from the soma and dendrites of hippocampal pyramidal neurons
under conditions of repetitive activation. Dendritic
K+ currents showed no activity-dependent change in
amplitude during trains of brief depolarizations. Dendritic
Na+ currents, however, displayed a striking decrease
in amplitude during such trains. The recovery from this attenuation was
slow and voltage-dependent. Somatic Na+ currents
also decreased during trains but to a much lesser degree. These results
represent the first electrophysiological evidence of regional
differences in somatic and dendritic Na+ channel
properties in pyramidal neurons (cf. Stuart and Sakmann, 1994; Magee
and Johnston, 1995).
The finding that somatic Na+ currents decrease
during trains, although to a lesser degree than dendritic
Na+ currents, seemed inconsistent with the constant
somatic action potential amplitude reported previously (Callaway and
Ross, 1995; Spruston et al., 1995; Tsubokawa and Ross, 1996a). Thus, we
tested whether factors other than the decrease in
Na+ current might contribute to the decrease in
dendritic action potential amplitude. We found that the relationship
between Na+ current and action potential amplitude
became stronger as the Na+/K+
permeability ratio decreased. Thus, in the dendrites, in which the
density of A-type K+ channels is high compared with
the density in the soma (Hoffman et al., 1997), the effect of losing
Na+ current during a train is more pronounced. Thus,
regional differences in both density and electrophysiological
properties of voltage-gated channels provide the basis for the
different activity dependence of somatic and dendritic action potential
amplitude.
Portions of this work have appeared in abstract form (Colbert and
Johnston, 1996a).
MATERIALS AND METHODS
Preparation and solutions. The present study used
4-10-week-old male Sprague Dawley rats. Animals were anesthetized with
a lethal dose of a combination of ketamine, xylazine, and acepromazine. Once deeply anesthetized, they were perfused through the heart with
cold, modified artificial CSF (ACSF) containing (in mM): 110 choline-Cl, 2.5 KCl, 1.2 NaH2PO4, 25 NaHCO3, 0.5 CaCl2, 7.0 MgCl2, and 20 dextrose. After removal of the brain,
400-µm-thick slices were cut using a Vibratome (Lancer), incubated
submerged in a holding chamber for 30 min at 32°C, and stored
submerged at room temperature.
During the slicing procedure, the slices were maintained in the same
ACSF used for the perfusion. The external recording solution contained
(in mM): 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 25 NaHCO3, 2.0 CaCl2, 1.0 MgCl2, and 25 dextrose. Slices were maintained in a submerged holding chamber in
normal external recording solution. All external solutions were bubbled
continuously with 95%O2/5%CO2. The
internal pipette solution used for whole-cell recordings contained (in
mM): 120 potassium gluconate, 20 KCl, 10 HEPES, 0.4 EGTA, 4.0 NaCl, 4.0 Mg2ATP, 0.3 Mg2GTP, and 14 phosphocreatine. pH was adjusted to 7.25 with KOH. The pipette solution
for cell-attached patch recordings of Na+ currents
contained (in mM): 120 NaCl, 30 tetraethylammonium (TEA) chloride, 10 HEPES, 2 CaCl2, 3 KCl, 1 MgCl2, and 5 4-aminopyridine (4-AP). pH was adjusted
to 7.4 with NaOH. For recording K+ currents, the
pipette contained (in mM): 125 NaCl, 10 HEPES, 2 CaCl2, 1 MgCl2, and 2.5 KCl, plus
1 µM tetrodotoxin (TTX). pH was adjusted to 7.4 with
NaOH.
Recording techniques. Recordings were made from somata and
dendrites of hippocampal CA1 pyramidal neurons. Neurons were visualized using infrared-illuminated, differential interference contrast (DIC)
optics (Axioskop; Ziess) according to standard techniques (Stuart et
al., 1993). Whole-cell patch recordings were made using microelectrode
amplifiers (Axoclamp 2A, Axon Instruments; IX2-700 Dagan Instruments)
in bridge mode. Cell-attached patch recordings were made using a
patch-clamp amplifier with a capacitive headstage (Axopatch 200A or 1D;
Axon Instruments). Pipettes (3-5 M for whole-cell and 7-12 M
for cell-attached) were made from borosilicate glass and pulled using a
P-87 Flaming-Brown pipette puller (Sutter Instruments). Except as
noted, cell-attached patch recordings were made submerged at room
temperature (~25°C). Membrane potentials were determined by
rupturing the patch after the channel data were recorded. Whole-cell
recordings were made submerged at ~35°C. Whole-cell series
resistance was 6-20 M for somatic recordings and 15-50 M for
dendritic recordings. Whole-cell recordings were low-pass filtered at 3 kHz (6 dB/octave) and digitized at 10 kHz. Cell-attached patch
recordings were filtered at 2 kHz (eight-pole Bessel filter) and
sampled at 10 kHz. Data were digitized at 16-bit resolution (ADC488/16;
IOTech) and stored by computer for off-line analysis (Next Computer).
Antidromic action potentials were stimulated by constant current pulses
(Neurolog; Digitimer Ltd. or WPI Instruments) through tungsten
electrodes (AM Systems) placed in the alveus. In some experiments,
trains of backpropagating action potentials were evoked by brief
depolarizing current pulses through the somatic electrode. Significance
was determined by t test with p < 0.05 considered significant. Data are reported as
mean ± SEM.
RESULTS
Dendritic action potential amplitudes decrease during trains
Simultaneous whole-cell recordings from the soma (Fig.
1A) and dendrites (Fig.
1B) of CA1 pyramidal neurons demonstrated a number of
differences between somatic and dendritic action potentials. First,
single action potentials were larger in the soma (88 ± 1.4 mV;
n = 8) than in the apical dendrites at ~200µm from
the soma (50 ± 4.5 mV; n = 8). Second, evoked at
rates of 5-50 Hz, action potentials maintained a relatively constant
amplitude in the soma (Vm, Fig.
1A) but decreased with successive action potentials in the dendrites (Vm, Fig.
1B). The amplitude ratio of the 10th to the first
action potential was 97 ± 1% (n = 8) in the soma
and 59 ± 2% in the dendrites. The maximum rate of rise of the
somatic action potential was more sensitive than its amplitude, revealing that the somatic action potential changed throughout the
train (dVm/dt, Fig.
1A,C). The
dVm/dt ratio of the 10th to the
first action potential was 86 ± 2%. In contrast, the rate of
rise of the dendritic action potential
(dVm/dt, Fig.
1B) decreased similarly to its amplitude (Fig.
1C). The dVm/dt ratio of the 10th to the first dendritic action potential was 50 ± 2%. Thus, action potentials displayed quite different activity dependencies in the soma and dendrites of CA1 pyramidal neurons.
Fig. 1.
Dendritic action potential amplitude and rate of
rise both decrease during repetitive activity. A,
Membrane potential Vm and its temporal
derivative dVm/dt during
a 20 Hz train of action potentials recorded from a CA1 pyramidal soma.
Action potential amplitude does not decrease although maximum rate of
rise decreases slightly during the train (dashed line,
dVm/dt of first spike).
B, Membrane potential Vm and its temporal derivative
dVm/dt during the same train of action potentials recorded simultaneously from the dendrite of the same CA1 pyramidal neuron used in
A. In the dendritic recording, both action potential
amplitude and maximum rate of rise drop significantly during the train
(dashed line, maximum
dVm/dt of first spike).
C, Grouped data comparing changes in somatic and
dendritic action potential (AP) amplitudes and maximum rates of rise.
Amount of change during the train is expressed by dividing the
amplitude of the 10th action potential in the train by the amplitude of
the first action potential (train frequency was 20-40 Hz). Note that
derivative traces are on an expanded time scale compared with the
voltage traces. Hash marks indicate where recordings
between action potentials were removed to compress the trace. Error
bars indicate SEM, and the numbers of recordings are shown in
parentheses. All recordings were simultaneous somatic
and dendritic recordings from the same neuron.
[View Larger Version of this Image (21K GIF file)]
Na+ channel current decreases during trains of
simulated action potentials
To identify the underlying changes in voltage-gated currents that
determine the frequency dependence of action potentials during trains,
we took the approach of observing pharmacologically isolated currents
in cell-attached patches of somatic and dendritic membranes. Patches
typically had 7-20 channels, estimated from peak currents and unitary
current amplitudes (Magee and Johnston, 1995; Hoffman et al., 1997). We
simulated trains of action potentials in the cell-attached patches by
trains (20 or 50 Hz) of brief depolarizations (2 msec; Fig.
2A). Ensemble averages
were constructed from 20-40 individual sweeps. The change in the
amplitudes of the ensemble currents was quantified as the relative
amplitude of the current evoked by the 10th step in the train compared
with the amplitude of the ensemble current evoked by the first
step.
Fig. 2.
Repetitive activity decreases available
Na+ current. A, To simulate trains of
action potentials, we gave trains of 10 depolarizing steps 2 msec in
duration to cell-attached patches at a frequency of 20 or 50 Hz.
Between depolarizations, the patch was held at either the resting
potential of the neuron or 20 mV hyperpolarized to the resting
potential of the neuron. 4-AP (5 mM) and TEA (30 mM) were included in the patch pipette to block
K+ channels. Soma waveform is a leak-subtracted
ensemble average of currents evoked by trains applied to a somatic
patch. The amplitude of the 10th evoked current is smaller than the
amplitude of the first evoked current. Rest potential recorded after
rupturing the patch was  63 mV. Dendrite waveform is a leak-subtracted
ensemble average of currents evoked by trains applied to a dendritic
patch. The amplitude of the 10th evoked current is greatly decreased compared with the first evoked current. Rest potential recorded after
rupture of the patch was 67 mV. B, First, fourth, and
10th evoked currents from A at expanded (1 msec) time
base. C, Group data. To quantify the decrease in current
amplitudes during the train, we reported the amplitude of the current
evoked by the 10th depolarizing step as a fraction of the amplitude of
the current evoked by the first depolarizing step. Top,
Group data for the 20 Hz train. Bottom, Group data for
the 50 Hz train. Error bars indicate SEM, and the numbers
above each bar indicate the numbers of patches. Open
bars correspond to trains from a hyperpolarized holding
potential. Filled bars correspond to trains from rest. Note that the decrease in Na+ current was always
greater in the dendrites. Note also that the decrease in both somatic
and dendritic Na+ channels was dependent on the
holding potential.
[View Larger Version of this Image (28K GIF file)]
The first channel type that we explored was the Na+
channel. As described in our previous studies (Magee and Johnston,
1995; Colbert and Johnston, 1996b), we isolated Na+
currents by including 4-AP and TEA in the patch pipette. Because of the
fast kinetics of Na+ channels, the channels
activated and substantially inactivated during the 2 msec command
potential (Fig. 2B). From a holding potential equal
to the resting potential of the cell (approximately 67 mV), ensemble
Na+ currents decreased in amplitude during trains.
Consistent with the change in
dVm/dt from the whole-cell
recordings (compare Fig. 1), the decrease was modest in somatic patches
but quite striking in dendritic patches (Soma and Dendrite, Fig.
2A,B). This difference was apparent
at both 20 and 50 Hz frequencies. In the dendrites, the ratio of the
10th current amplitude to the first was 38 ± 3%
(n = 16) during the 50 Hz train and 37 ± 3% (n = 11) during the 20 Hz train (Fig. 2C).
Na+ currents evoked in somatic patches decreased to
63 ± 5% (n = 11) at 50 Hz and 73 ± 4%
(n = 12) at 20 Hz.
To determine whether the decrease in Na+ current
during trains was dependent on holding potential, we held the patch at
20-30 mV hyperpolarized to its rest potential. With the hyperpolarized holding potential, the Na+ current decreased
significantly less than when held at rest (Fig. 2C). In the
soma the current decreased by the 10th step to 85 ± 3%
(n = 4) at 50 Hz and to 84 ± 3%
(n = 10) at 20 Hz. In the dendrites the current
decreased to 49 ± 6% (n = 7) at 50 Hz and to
47 ± 4% (n = 5) at 20 Hz. Thus, the decrease in
both somatic and dendritic Na+ channels was
voltage-dependent. The difference in the magnitude of the decrease in
the soma and dendrites, however, could not be explained by differences
in resting potential. Even when held at 20 mV hyperpolarized to rest,
the dendritic Na+ currents decreased more than the
somatic Na+ currents held at rest.
Spruston et al. (1995) reported that the recovery of action potential
amplitude in the dendrites after a train of action potentials was slow
and voltage-dependent. If the loss of Na+ current
during trains was responsible for the loss of action potential
amplitude in the dendrites, then the recovery of the Na+ current amplitude after a train should be slow
as well. To test this hypothesis, we observed the recovery of
Na+ current amplitude after a 20 Hz train of brief
depolarizations. After giving a train, we waited a variable length of
time (100, 400, 800, or 1600 msec) and then gave a final brief test
depolarization (Fig. 3A). The
minimum duration before a new train was given was 5 sec. To quantify
the time course of recovery, we first normalized the amplitude of each
test current in the train to the amplitude of the first current. We
then scaled the amplitude of each test current (Fig. 3B)
between the amplitude of the 10th current in the 20 Hz train (i.e., 0%
recovery) and the amplitude of the first current in the 20 Hz train
(i.e., 100% recovery). Finally, these normalized values were fit with
single exponentials to determine an approximate time constant of
recovery. Dendritic Na+ currents recovered at rest
potential with a single-exponential time constant of 5.6 sec (Fig.
3C, Dendrite). Somatic Na+ currents
recovered with a single-exponential time constant of 4.1 sec (Soma,
Fig. 3C). That the time constant of recovery for the
Na+ current was measured in seconds suggests that
the decrease in Na+ current was more consistent with
reported slow inactivations of the Na+ channel than
with accumulation of fast inactivation (see Discussion).
Fig. 3.
Recovery of Na+ current after a
train is slow and voltage-dependent. A, To measure the
rate of recovery of available Na+ current, we
decreased Na+ current to 10 mV by a 20 Hz train of
10 depolarizing steps each of 2 msec duration. Each train was followed
by a single test depolarization after a wait of 100, 400, 800, or 1600 msec. B, Waveforms are leak-subtracted ensemble currents
during the recovery paradigm. The first evoked current in the train
represents the maximum (control) amplitude of the evoked current. At
the end of the train, the 10th evoked current is decreased in
amplitude. The amplitude of the current recovers as the duration of the
waiting period (100-1600) is increased. C, Group data
for recovery from holding potentials at rest and at 20-30 mV
hyperpolarized to rest. Top, Dendritic patches.
Bottom, Somatic patches. Values of the test currents are
scaled between the amplitude of the current evoked by the 10th
depolarizing step in the train (0% recovery) and the amplitude of the
current evoked by the first depolarizing step (100% recovery). Note
that the recovery of currents in both somatic and dendritic patches was
slow and voltage-dependent. Error bars indicate SEM, and the numbers of
patches are in parentheses.
[View Larger Version of this Image (16K GIF file)]
To test for voltage dependence of recovery, we repeated the recovery
paradigm using a holding potential 20-30 mV hyperpolarized from rest.
At this holding potential, the rate of recovery increased in both
somatic and dendritic patches (Fig. 3C). The
single-exponential time constant of recovery was 0.79 sec for somatic
patches and 2.2 sec for dendritic patches. As seen with the magnitude
of the decrease in Na+ current, the voltage
dependence of recovery of Na+ current seemed to
differ between somatic and dendritic patches.
K+ currents remain constant during trains
After identifying the activity dependence of
Na+ channels in cell-attached patches, we turned to
the observation of K+ channels. From a negative
holding potential, a long step to +40 mV evoked an outward current with
two major components: a fast transient A-type current and a smaller
sustained delayed-rectifier-type (DR-type) component (Fig.
4A). We have
characterized these currents previously and found them to be the
dominant outward currents in dendritic patches from CA1 pyramidal cells
(Hoffman et al., 1997).
Fig. 4.
Repetitive activity does not alter available
K+ current. A, Waveform is a
leak-subtracted ensemble average of K+ current in a
cell-attached dendritic patch (~150 µm) evoked by a step to a
depolarized command potential for 100 msec. The waveform demonstrates
the early fast transient A-type current and a sustained DR-type current
typical of dendritic patches. B, Top, To
test whether repetitive activity alters available K+
channels, we applied trains of brief depolarizations to a patch as
described in A from a holding potential near rest to a
potential of 10 mV. Bottom, Waveform is a
leak-subtracted ensemble current during the train. Note that the
currents rapidly inactivate at the end of each step and that there is
no current between steps. C, First, fourth, and eighth
evoked currents from B at expanded (2 msec) time base.
Note in B and C that there is no
alteration of current amplitude throughout the train. Note also that to
account for a decrease in dendritic action potential amplitude during a
train, the K+ currents would be expected to
increase in amplitude throughout the train.
[View Larger Version of this Image (15K GIF file)]
As described for the Na+ channels, we tested the
activity dependence of the K+ channels by simulating
trains of action potentials with trains of brief depolarizations of
dendritic cell-attached patches. Trains of 8-10 brief depolarizations
from rest to +40 mV resulted in essentially no change in the evoked
current between the first and the last depolarization (0.98 ± 0.02). To provide a better comparison with the Na+
current experiments and to simulate a dendritic action potential, we
repeated the trains in some patches from rest to 10 mV (Fig. 4B,C). We also tried a number of
different combinations of frequency and duration of the steps (up to 30 msec; data not shown). In all cases there was no change in the outward
current during the train. The outward current deactivates very rapidly
at the end of the 2 msec depolarization, and there does not seem to be
any residual current in the waveform between the depolarizing steps (Fig. 4B,C). These experiments
additionally provide a useful technical control for the
Na+ channel experiments; there is no recording
artifact that results in an apparent alteration of currents during a
train.
Hyperpolarization between action potentials reduces the decrease in
action potential amplitude during trains
The results of the cell-attached patch experiments suggested that
trains of action potentials in CA1 pyramidal neurons lead to a slowly
recovering, voltage-dependent decrease in available Na+ current but no long-lasting change in
K+ currents. To test the role of this decrease in
Na+ current on action potential amplitude during
trains, we gave transient hyperpolarizing current injections, via the
dendritic pipette, between each individual action potential in a train. Such membrane hyperpolarization should reduce Na+
channel inactivation during the train, allowing action potential amplitude and maximum rate of rise to be maintained. Hyperpolarizations of 20-25 mV (Fig. 5A, arrow
S) produced a graded effect on the attenuation of action potential
amplitude, whereas even larger hyperpolarizations of 35-45 mV (Fig.
5A, arrow L) completely eliminated the decrease in action
potential amplitude (3 ± 2% decrease; n = 5) and
rate of rise (11 ± 7% decrease; n = 5) that
normally occurred during trains (Fig. 5A, arrow C). We
repeated a similar paradigm at the same temperature as the whole-cell
experiments using the cell-attached patches. Forty msec, 40 mV
hyperpolarizing steps were given during the period between test
commands to 10 mV in a train as described in Figure
2A. Without the hyperpolarizing steps, the
attenuation was 55 ± 3% (n = 3). With the
hyperpolarizing steps, the attenuation was reduced to 20 ± 1%
(n = 3). The agreement between the channel data and the
maximum rate of rise is consistent with the notion that the
Na+ channels underlie the activity-dependent
decrease in action potential amplitude.
Fig. 5.
Membrane hyperpolarization modulates action
potential amplitude decrement during trains. A, A train
of action potentials (17 Hz) recorded from a CA1 dendrite (~200 µm)
with (light traces) and without (dark
traces) the presence of membrane hyperpolarizations between the
spikes. The largest hyperpolarizations (35-45 mV; 2.0 nA; 40 msec;
arrow L) completely removed the decrease in action potential amplitude, whereas smaller hyperpolarizations (20-25 mV; 1.5 nA; 40 msec; arrow S) produced a graded effect on
amplitude. The final action potential without interspersed
hyperpolarizations is indicated by arrow C.
B, Grouped data comparing changes in dendritic action
potential amplitudes and maximum rates of rise with (open
bars) and without (filled bars) ~40 mV
hyperpolarizations between action potentials. Amount of change during
the train is expressed by dividing the amplitude of the last action
potential in the train (8th-10th) by the amplitude of the first action
potential (train frequency was 20-40 Hz). Records were truncated
between action potentials to compress the length of the
trace. Error bars indicate SEM, and the numbers of
recordings are shown in parentheses.
[View Larger Version of this Image (23K GIF file)]
We have found previously that in CA1 pyramidal neurons the dendritic
A-type K+ channel density increases linearly with
distance from the soma to reach a value fivefold higher than that found
in the soma (Hoffman et al., 1997). Thus, we wanted to investigate the
role of the relatively high density of dendritic A-type
K+ channels in the decrease of action potential
amplitude during trains. The elevated A-channel density determines that
dendritic membrane has a Na+/K+
permeability ratio that is significantly lower than that of somatic membrane. As a result, similar reductions in Na+
current could potentially result in greater attenuation of action potential amplitude in the dendrites. We bath applied 4-AP (3-8 mM) to reduce the density of A-type K+
channels, diminishing the somatodendritic gradient of
Na+/K+ permeability.
Cd2+ at 200 µM was also included to
reduce Ca2+ spikes. After application of 4-AP, the
decrease in action potential amplitude was reduced from 41 ± 3%
to 15 ± 2% (n = 5; Fig.
6A,B), whereas the decrease in maximum rate of rise remained unchanged at
50 ± 3% (n = 5) for control versus 51 ± 4% (n = 5) with 4-AP application. These data suggest
that without the high density of dendritic K+
current, the decrease in Na+ current during a train
of spikes [which was unchanged by 4-AP application (see
dVm/dt plot in Fig.
4B)] is less effective in reducing action potential
amplitude. Thus, along with the Na+ channel
inactivation observed in the dendrites, the elevated dendritic
A-channel density enhances the decrease in action potential amplitude
during trains.
Fig. 6.
Manipulation of the
Na+/K+ permeability ratio
modulates action potential decrement during trains. A, A
train of action potentials (33 Hz) recorded from a CA1 dendrite (~240
µm) before (dark traces) and after (light
traces) bath application of 8 mM 4-AP showing that
high concentrations of 4-AP allowed action potential amplitude to
remain fairly constant during repetitive stimulation. B,
Grouped data showing that with a reduced K+
permeability (filled bars) dendritic action
potential amplitude remains fairly constant during a train, although
the substantial decrease in maximum rate of rise remains unchanged
(control, open bars). C, A train of
action potentials (20 Hz) recorded from a CA1 soma before (light
traces) and after (dark traces) bath application of 100 nM TTX showing that low concentrations of TTX
increased the amount of action potential amplitude decrement during
repetitive stimulation. D, Grouped data showing that
with a reduced Na+ permeability
(filled bars) somatic action potential amplitude is substantially reduced during a train of repetitive activity, although the decrease in the maximum rate of rise is only slightly greater (control, open bars). Amount of change during
the train is expressed by dividing the amplitude of the last action
potential in the train (8th-10th) by the amplitude of the first action
potential (train frequency was 20-40 Hz). Records between action
potentials were truncated to compress the length of the
trace. Error bars indicate SEM, and the numbers of
recordings are shown in parentheses.
[View Larger Version of this Image (25K GIF file)]
To test this idea further, we lowered the relatively high
Na+/K+ permeability ratio of the
somatic membrane by applying a low concentration of TTX (100 nM) to the bath (Fig. 6C,D). TTX
increased the drop-off in somatic action potential amplitude during a
train from 4 ± 1% to 18 ± 3% (n = 5).
Furthermore, there was a greater decrease in the maximum
dVm/dt: 21 ± 2%
(n = 5) for control versus 33 ± 4%
(n = 5) with TTX application. Thus, lowering the Na+ channel density of somatic membrane allowed the
~20% decrease in Na+ current occurring during a
train to have a more pronounced affect on somatic action potential
amplitude. However, even in the presence of TTX, the decrease in
somatic action potential amplitude was never as great as that recorded
in the dendritic regions under control conditions (21% in the soma vs
41% in the dendrites).
DISCUSSION
In the present study, we have identified properties of ion
channels that taken together predict the different activity dependence of action potential amplitude in the soma and apical dendrites of CA1
pyramidal neurons. First, repetitive activation of
Na+ channels leads to a loss of available
Na+ current that has a slow and voltage-dependent
rate of recovery. The magnitude of this loss of current seems to be
considerably greater in the dendrites than in the soma. Second, the
degree to which action potential amplitude depends on the magnitude of Na+ current is a function of the
Na+/K+ permeability ratio.
Therefore, the relatively high density of A-type K+
channels and the relatively greater decrease in Na+
current in the dendrites determine that backpropagation of action potentials into the dendritic arborization will be severely reduced during repetitive firing.
Slow Na+ channel inactivation
Slowly accumulating inactivation and slow recovery from
inactivation have been described in Na+ channels
from a number of preparations including skeletal muscle (Ruff et al.,
1988), squid giant axon (Moore et al., 1964; Rudy, 1978),
suprachiasmatic neurons (Huang, 1993), and most recently neocortical
neurons (Fleidervish et al., 1996). Importantly, slow inactivation of
Na+ channels has traditionally been associated with
long-sustained depolarizations. Because of this association, its role
as a physiological or even pathophysiological process has been
questioned (Cannon, 1996). In the present study, however, the slow
inactivation state is rapidly entered (i.e., within a single train)
and, thus, is likely to have a physiological role (see below).
Fleidervish et al. (1996) described previously a slow inactivation of
Na+ channels in somata of neocortical pyramidal
neurons. Using somatic recordings, they found that multiple long
depolarizations (>500 msec) decreased somatic firing frequency. Using
cell-attached patches on the soma, they found that a single
depolarization to approximately 10 mV required 2 sec duration to
inactivate 50% of the current. Recovery from this inactivation had a
rate constant similar to that seen in the present study and, thus, may
represent the same process. Fleidervish et al. suggested that such slow inactivation may explain the activity dependence of dendritic action
potential amplitude (Callaway and Ross, 1995; Spruston et al., 1995).
The present findings make this suggestion more plausible. First, we
showed that a single train of brief depolarizations, rather than
sustained depolarization, greatly decreases Na+
current in dendritic patches. Second, we demonstrated that the relatively low K+ channel density in the soma
together with the more modest decrease in somatic
Na+ current predicts the modest activity dependence
of somatic action potential amplitude. Importantly, this scheme
reconciles the experimentally observed uniform density of
Na+ channels throughout the dendrites, soma, and
initial segment (Magee and Johnston, 1995; Colbert and Johnston, 1996b)
with the notion of different
Na+/K+ permeability ratios in
these regions. Traditionally, electrophysiological properties of
pyramidal neurons consistent with a high
Na+/K+ permeability ratio have
been attributed to an extremely high density of Na+
channels in the axon.
Differences in Na+ inactivation between soma
and dendrites
The observed differences in the attenuation of
Na+ current in the soma and dendrites imply regional
differences in either the type of channels or their modulation. In
previous electrophysiological studies of Na+
channels in pyramidal neurons (Stuart and Sakmann, 1994; Magee and
Johnston, 1995), no regional differences were noted in the steady-state
or kinetic properties of activation or fast inactivation to suggest
different channel types. Although there is evidence of segregation of
Na+ channel  -subunits within the neuron [i.e., a
relatively high density of type I in the somatic region and a
relatively high density of type II or IIA in fiber tracts (Westenbroek
et al., 1989)], type IIA apparently accounts for ~80% of the total
in all regions. Furthermore, because it is difficult to distinguish the
presynaptic or postynaptic location of the subunits in the dendritic
fields, it is not clear whether the distribution of -subunits can
account for the regional differences in electrophysiological properties
of the Na+ channels reported here.
A number of modulations of the voltage dependence of activation and
fast inactivation have been reported (reviewed in Catterall, 1992),
including phosphorylation by protein kinase C (Renganathan et al.,
1995; Cantrell et al., 1996) and by cAMP-dependent pathways (Li et al.,
1992). Effects of these various pathways have been studied primarily in
somata or in expression systems; thus differences in regional activity
of the various modulators are not known. Regional differences in the
activity of the various modulatory systems would provide an explanation
for the differences in the magnitude of Na+ current
attenuation seen here without the need to invoke regional differences
in Na+ channel subtypes.
Functional consequences
The decrease in dendritic action potential amplitude represents a
time- and activity-dependent process. It is important to note that the
rates of action potential generation that decrease dendritic action
potential amplitude include not only high frequency burst firing but
also sustained firing that is not much above background rates
(Tsubokawa and Ross, 1997). Spikes that occur at 5-10 Hz will cause
significant reductions in dendritic Na+ current.
Furthermore, these reductions will impact not only action potential
amplitude but any process that depends on Na+
current, such as boosting of EPSPs or setting thresholds for action
potential initiation. Although we demonstrated that a significant block
of A-type K+ channels greatly minimized the effect
of Na+ current attenuation on spike amplitude,
significant activity-dependent attenuation of dendritic spikes still
occurs under less extreme conditions in which inactivation of A-type
channels boosts the amplitude of the early spikes in the train
(Andreasen and Lambert, 1995; Spruston et al., 1995).
A decrease in the influx of Ca2+ ions
accompanies any decrease in dendritic action potential amplitude (Jaffe
et al., 1992; Callaway and Ross, 1995; Spruston et al., 1995; Tsubokawa
and Ross, 1996b). Therefore, any process that depends on the influx of
Ca2+ will be affected by changes in dendritic action
potential amplitude. Although the relationships between
Ca2+ influx and processes such as long-term
potentiation are not fully understood, the backpropagating dendritic
action potential has been demonstrated to be an important postynaptic
signal for the induction of such processes (Magee and Johnston, 1997;
Markram et al., 1997). Thus, it is probable that regulation of
dendritic spike amplitude determines some of the activity dependence of the induction of various synaptic plasticities. The present result that
both Na+ and K+ channels
contribute to the expression of the decrease in dendritic action
potential amplitude suggests two independent targets for modulation of
dendritic action potential amplitude by second-messenger systems
(Tsubokawa and Ross, 1997).
FOOTNOTES
Received April 11, 1997; revised June 6, 1997; accepted June 11, 1997.
This work was supported by NS11535, MH44754, MH48432, and Human
Frontiers in Science Program to D.J.
Correspondence should be addressed to Dr. Costa M. Colbert, Division of
Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX
77030.
Dr. Magee's present address: Neuroscience Center, Louisiana State
University, Medical Center, 2020 Gravier, New Orleans, LA 70112.
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Experience-Dependent Changes in Extracellular Spike Amplitude May Reflect Regulation of Dendritic Action Potential Back-Propagation in Rat Hippocampal Pyramidal Cells
J. Neurosci.,
January 1, 2001;
21(1):
240 - 248.
[Abstract]
[Full Text]
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S. R. Williams and G. J. Stuart
Backpropagation of Physiological Spike Trains in Neocortical Pyramidal Neurons: Implications for Temporal Coding in Dendrites
J. Neurosci.,
November 15, 2000;
20(22):
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[Abstract]
[Full Text]
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N. P. Staff, H.-Y. Jung, T. Thiagarajan, M. Yao, and N. Spruston
Resting and Active Properties of Pyramidal Neurons in Subiculum and CA1 of Rat Hippocampus
J Neurophysiol,
November 1, 2000;
84(5):
2398 - 2408.
[Abstract]
[Full Text]
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M. Häusser, N. Spruston, and G. J. Stuart
Diversity and Dynamics of Dendritic Signaling
Science,
October 27, 2000;
290(5492):
739 - 744.
[Abstract]
[Full Text]
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S.-I. Watanabe, A. Koizumi, S. Matsunaga, J. W. Stocker, and A. Kaneko
GABA-Mediated Inhibition Between Amacrine Cells in the Goldfish Retina
J Neurophysiol,
October 1, 2000;
84(4):
1826 - 1834.
[Abstract]
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N. Lemon and R. W. Turner
Conditional Spike Backpropagation Generates Burst Discharge in a Sensory Neuron
J Neurophysiol,
September 1, 2000;
84(3):
1519 - 1530.
[Abstract]
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J J. Zhu
Maturation of layer 5 neocortical pyramidal neurons: amplifying salient layer 1 and layer 4 inputs by Ca2+ action potentials in adult rat tuft dendrites
J. Physiol.,
August 1, 2000;
526(3):
571 - 587.
[Abstract]
[Full Text]
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J. M. Schjott and M. R. Plummer
Sustained Activation of Hippocampal Lp-Type Voltage-Gated Calcium Channels by Tetanic Stimulation
J. Neurosci.,
July 1, 2000;
20(13):
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[Abstract]
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H. Tsubokawa, S. Offermanns, M. Simon, and M. Kano
Calcium-Dependent Persistent Facilitation of Spike Backpropagation in the CA1 Pyramidal Neurons
J. Neurosci.,
July 1, 2000;
20(13):
4878 - 4884.
[Abstract]
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R. Azouz and C. M. Gray
Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo
PNAS,
June 14, 2000;
(2000)
130200797.
[Abstract]
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D. Johnston, D. A Hoffman, J. C Magee, N. P Poolos, S. Watanabe, C. M Colbert, and M. Migliore
Dendritic potassium channels in hippocampal pyramidal neurons
J. Physiol.,
May 15, 2000;
525(1):
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[Abstract]
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L. Lopez-Aguado, J. M. Ibarz, and O. Herreras
Modulation of Dendritic Action Currents Decreases the Reliability of Population Spikes
J Neurophysiol,
February 1, 2000;
83(2):
1108 - 1114.
[Abstract]
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S. R Williams and G. J Stuart
Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons
J. Physiol.,
December 1, 1999;
521(2):
467 - 482.
[Abstract]
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C. M. Colbert and E. Pan
Arachidonic Acid Reciprocally Alters the Availability of Transient and Sustained Dendritic K+ Channels in Hippocampal CA1 Pyramidal Neurons
J. Neurosci.,
October 1, 1999;
19(19):
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[Abstract]
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V. Sourdet and D. Debanne
The Role of Dendritic Filtering in Associative Long-Term Synaptic Plasticity
Learn. Mem.,
September 1, 1999;
6(5):
422 - 447.
[Abstract]
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N. P. Poolos and D. Johnston
Calcium-Activated Potassium Conductances Contribute to Action Potential Repolarization at the Soma But Not the Dendrites of Hippocampal CA1 Pyramidal Neurons
J. Neurosci.,
July 1, 1999;
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[Abstract]
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D. A. Hoffman and D. Johnston
Neuromodulation of Dendritic Action Potentials
J Neurophysiol,
January 1, 1999;
81(1):
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[Abstract]
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T. R. Cummins, J. R. Howe, and S. G. Waxman
Slow Closed-State Inactivation: A Novel Mechanism Underlying Ramp Currents in Cells Expressing the hNE/PN1 Sodium Channel
J. Neurosci.,
December 1, 1998;
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[Abstract]
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G. C. Tombaugh
Intracellular pH Buffering Shapes Activity-Dependent Ca2+ Dynamics in Dendrites of CA1 Interneurons
J Neurophysiol,
October 1, 1998;
80(4):
1702 - 1712.
[Abstract]
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P. J. Mackenzie and T. H. Murphy
High Safety Factor for Action Potential Conduction Along Axons But Not Dendrites of Cultured Hippocampal and Cortical Neurons
J Neurophysiol,
October 1, 1998;
80(4):
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[Abstract]
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N. Astman, M. J. Gutnick, and I. A. Fleidervish
Activation of Protein Kinase C Increases Neuronal Excitability by Regulating Persistent Na+ Current in Mouse Neocortical Slices
J Neurophysiol,
September 1, 1998;
80(3):
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[Abstract]
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D. A. Hoffman and D. Johnston
Downregulation of Transient K+ Channels in Dendrites of Hippocampal CA1 Pyramidal Neurons by Activation of PKA and PKC
J. Neurosci.,
May 15, 1998;
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[Abstract]
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G Reckziegel, H Beck, J Schramm, C E Elger, and B W Urban
Electrophysiological characterization of Na+ currents in acutely isolated human hippocampal dentate granule cells
J. Physiol.,
May 15, 1998;
509(1):
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[Abstract]
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C. M. Colbert and D. Johnston
Protein Kinase C Activation Decreases Activity-Dependent Attenuation of Dendritic Na+ Current in Hippocampal CA1 Pyramidal Neurons
J Neurophysiol,
January 1, 1998;
79(1):
491 - 495.
[Abstract]
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S. Charpak, J. Mertz, E. Beaurepaire, L. Moreaux, and K. Delaney
Odor-evoked calcium signals in dendrites of rat mitral cells
PNAS,
January 30, 2001;
98(3):
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[Abstract]
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R. Azouz and C. M. Gray
Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo
PNAS,
July 5, 2000;
97(14):
8110 - 8115.
[Abstract]
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