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Volume 17, Number 17,
Issue of September 1, 1997
pp. 6639-6646
Copyright ©1997 Society for Neuroscience
Prolonged Sodium Channel Inactivation Contributes to Dendritic
Action Potential Attenuation in Hippocampal Pyramidal Neurons
Hae-Yoon Jung ,
Timothy Mickus , and
Nelson Spruston
Department of Neurobiology and Physiology, Institute for
Neuroscience, Northwestern University, Evanston, Illinois
60208-3520
ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
During low-frequency firing, action potentials actively invade the
dendrites of CA1 pyramidal neurons. At higher firing rates, however,
activity-dependent processes result in the attenuation of
back-propagating action potentials, and propagation failures occur at
some dendritic branch points. We tested two major hypotheses related to
this activity-dependent attenuation of back-propagating action
potentials: (1) that it is mediated by a prolonged form of sodium
channel inactivation and (2) that it is mediated by a persistent
dendritic shunt activated by back-propagating action potentials. We
found no evidence for a persistent shunt, but we did find that
cumulative, prolonged inactivation of sodium channels develops during
repetitive action potential firing. This inactivation is significant
after a single action potential and continues to develop during several
action potentials thereafter, until a steady-state sodium current is
established. Recovery from this form of inactivation is much slower
than its induction, but recovery can be accelerated by
hyperpolarization. The similarity of these properties to the time and
voltage dependence of attenuation and recovery of dendritic action
potentials suggests that dendritic sodium channel inactivation contributes to the activity dependence of action potential
back-propagation in CA1 neurons. Hence, the biophysical properties of
dendritic sodium channels will be important determinants of action
potential-mediated effects on synaptic integration and plasticity in
hippocampal neurons.
Key words:
dendrite;
action potential;
sodium channels;
synaptic
integration;
pyramidal neuron;
activity dependent
INTRODUCTION
Recent experiments using
simultaneous somatic and dendritic patch-pipette recordings have shown
that action potentials are normally initiated in the axon and
back-propagate into the dendrites of many types of CNS neurons (for
review, see Stuart et al., 1997
). These back-propagating action
potentials are likely to provide an important spatial signal that
influences ongoing synaptic integration and allows for postsynaptic
firing in the axon to be associated with presynaptic activity. For
example, the induction of activity-dependent changes in synaptic
strength such as long-term potentiation (LTP) and long-term depression
depend critically on the timing of pre- and postsynaptic inputs (Levy
and Steward, 1983; Markram et al., 1997), and one form of LTP has been
shown to be blocked by preventing action potentials from
back-propagating into the dendrites of hippocampal pyramidal neurons
(Magee and Johnston, 1997). These findings demonstrate the importance
of understanding the factors that determine the extent and pattern of
action potential back-propagation in pyramidal neuron dendrites.
Action potential back-propagation in CA1 dendrites is complex. At low
frequencies action potentials invade most of the dendritic tree in an
active fashion, whereas at higher frequencies action potentials
attenuate more and may fail to actively propagate into much of the
dendritic tree (Callaway and Ross, 1995; Spruston et al., 1995). The
degree of action potential attenuation observed during a train of
action potentials depends on the location of the recording in the
dendritic tree, the number of action potentials, and the rate of
firing. In distal dendrites, dramatic attenuation of action potential
amplitude typically occurs after one or a few action potentials at 20 Hz, and apparent failures of active propagation are often observed at
branch points, whereas attenuation is smaller and more gradual in
proximal dendrites. The degree of dendritic action potential
attenuation is also known to be dependent on the membrane potential
between action potentials (Spruston et al., 1995), suggesting that the
states of dendritic voltage-gated channels are important determinants
of how action potentials spread through the dendrites. The identity of
these channels, however, and their effects on action potential
back-propagation are obscure. Here we describe experiments that examine
the role of voltage-gated channels in the back-propagation of action
potentials into the dendrites of CA1 pyramidal neurons in
vitro.
MATERIALS AND METHODS
Slice preparation. Hippocampal slices were prepared
from the brains of 14- to 45-d-old Wistar rats, which were decapitated after halothane anesthesia. Slices were cut 300 µm thick using a
vibrating tissue slicer (Campden Instruments). During the dissection and slicing procedure, brains were kept in an ice-cold physiological solution. Slices were transferred to a holding chamber containing the
same physiological solution at 35-37°C for 30-45 min and
subsequently at room temperature. For recording, slices were
transferred individually to a chamber and perfused with physiological
solution at 33-37°C.
Patch-pipette recording. Slices were visualized using
infrared differential interference microscopy (Stuart et al., 1993) using a fixed-stage microscope (Zeiss Axioscop) and a Newvicon camera
(Dage MTI). Patch-pipette recordings were obtained under visual control
on the soma or dendrites of pyramidal neurons in the CA1 region of
hippocampus. High-resistance seals (2-20 G
) were formed using
fire-polished electrodes (thick-walled, borosilicate glass EN-1; Garner
Glass Co.) pulled to tip resistances of 3-8 M (Brown-Flaming
P30 puller, Sutter Instrument Co.). Experiments were performed in
whole-cell, cell-attached, or nucleated-patch configurations. In the
whole-cell configuration, recordings were obtained in the current-clamp
mode, series resistance (20-50 M) was compensated with a bridge
circuit, and capacitance compensation was performed. Nucleated patches
were obtained by forming whole-cell recordings from somata near the
surface of the slice and then withdrawing the pipette with negative
pressure (0.5-1.5 psi) applied to the pipette (Sather et al., 1992).
This resulted in the formation of large outside-out patches of membrane
surrounding the nucleus. Whole-cell and nucleated-patch recordings were
performed at 33-37°C; dendrite-attached patch recordings were
performed at 27-36°C. For voltage-clamp experiments, electrodes were
coated with Sylgard to reduce electrode capacitance, and the remaining
patch-pipette capacitance was compensated.
Solutions and drugs. External physiological solution
consisted of (in mM): 125 NaCl, 2.5 KCl, 25 NaHCO3, 1.25 NaH2PO4,
1 MgCl2, 2 CaCl2, 25 dextrose.
Pipette solutions for the different recording configurations were as
follows (in mM): whole-cell recording: 115 potassium
gluconate, 20 KCl, 10 phosphocreatine (disodium salt), 10 HEPES, 10 EGTA, 4 MgATP, 0.3 NaGTP, pH 7.3 with KOH; cell-attached recording: 120 NaCl, 3 KCl, 10 HEPES, 2 CaCl2, 1 MgCl2, 30 tetraethylammonium chloride (TEA), 5 4-aminopyridine (4-AP), pH 7.4 with NaOH; nucleated-patch recording:
130 CsCl, 10 phosphocreatine (disodium salt), 2 MgCl2, 10 HEPES, 0.2 EGTA, 4 Na2ATP, pH
7.4 with KOH. In some cases creatine phosphokinase (50 U/ml) was also
included in the pipette solution. In most nucleated-patch experiments,
30 mM TEA and 5 mM 4-AP were added to the bath,
but outward currents were negligible even in the absence of these external K+ channel blockers. Some rundown of patch
current was observed in nucleated-patch experiments. The first response
in each train was monitored over time, and trials were rejected if this
first response was less than two-thirds of the amplitude measured at the beginning of the experiment.
Data acquisition and analysis. Current-clamp recordings were
obtained with Dagan BVC-700 amplifiers; voltage was filtered at 5 kHz
and digitized at 10 kHz. Voltage-clamp recordings (nucleated- and
cell-attached patches) were obtained with Axoclamp 1D and Axoclamp 200A
amplifiers; current was filtered at 2 kHz and sampled at 50 kHz. Data
acquisition was performed using Pulse Control software (R. Bookman,
University of Miami) running under Igor Pro 3.0 (Wavemetrics) on
Macintosh Power PC computers (Apple Computer) equipped with ITC-16
hardware interfaces (Instrutech Corp.). Capacitance and leak
subtraction was performed by adding the current response to the test
command with four responses to an inverted command potential one-fourth
of the test command amplitude (i.e., 
P/4 subtraction). Data analysis
was performed using Igor Pro. All values are reported as mean ± SEM.
RESULTS
Action potentials recorded in the whole-cell configuration from
the soma and dendrite (120 µm from the soma) of different CA1
pyramidal neurons are shown in the top traces of Figure
1A,B. The
activity-dependent attenuation of back-propagating action potentials
reported previously (Callaway and Ross, 1995; Spruston et al., 1995) is
evident in this dendritic recording (Fig. 1B, top trace), obtained from a neuron maintained at 34°C in a
slice from an 18-d-old rat. We tested two major hypotheses regarding the mechanisms underlying this activity-dependent action potential attenuation: (1) that attenuation is mediated by a form of
Na+ channel inactivation developing as action
potentials fire and (2) that attenuation is mediated by a dendritic
shunt that develops as action potentials fire.
Fig. 1.
Cumulative, prolonged inactivation of
Na+ currents in nucleated patches. A,
A command potential consisting of a previously recorded train of
somatic action potentials evokes voltage-gated Na+
currents in a nucleated patch. Each action potential evokes
Na+ currents that inactivate but do not fully
recover during the ~50 msec interspike interval, leading to a decline
in Na+ current amplitude attributable to cumulative
inactivation. B, A train of action potentials recorded
from the apical dendrite (120 µm from the soma) of a different cell
also evokes Na+ currents exhibiting cumulative,
prolonged inactivation. C, Cumulative, prolonged
Na+ current inactivation is also observed during
repetitive depolarizations of 70 mV amplitude and 2 msec duration.
Recordings in A-C are from the same nucleated patch and
are averages of three to six trials.
[View Larger Version of this Image (27K GIF file)]
To test the first hypothesis, Na+ currents were
examined in either cell-attached or nucleated patches (Sather et al.,
1992). Inward currents were elicited by transient depolarizations using either a previously recorded train of action potentials or a series of
2-5 msec depolarizations as the command potential. These currents were
mediated by TTX-sensitive Na+ channels (see text
below) and hence are termed INa. To measure the
currents during realistic depolarizations, trains of action potentials
recorded from the soma or the dendrite in the whole-cell configuration
(Fig. 1A,B, top traces) were stored and later used as
command potentials to depolarize nucleated patches. This protocol allowed us to determine the nature of INa that
would be flowing during normal action potential firing. The resulting
patch current shows that the INa in response to
repetitive action potential firing becomes progressively smaller during
the train (Fig. 1A). When a dendritically recorded
train of action potentials is used as the command in the same patch,
the current attenuation is greater, as predicted because of the
progressive decrease in action potential amplitude during the train
(Fig. 1B).
Although these experiments demonstrate that INa
is expected to decrease during successive action potentials in a train,
the reasons for this remain unclear from this experiment. One
possibility is that some Na+ channel inactivation
occurs that is slow to recover, but the slower rise of later action
potentials may also contribute to the reduced
INa during action potential commands. To
determine whether inactivation does in fact contribute,
INa was also examined in response to trains of
2-5 msec step depolarizations at 20 Hz. Figure 1C shows
that during such a command potential, significant inactivation of
INa indeed occurs. These findings support the hypothesis that Na+ channel inactivation contributes
to the attenuation of back-propagating action potentials. The first
action potential leaves a fraction of dendritic Na+
channels in the inactivated state, so the second action potential attenuates more as it propagates along the dendrite. At any dendritic location, a reduced Na+ current flows as a result of
the prolonged Na+ channel inactivation and the
smaller amplitude of the upstream action potential.
That the currents observed in experiments like those shown in Figure 1
were indeed Na+ currents was confirmed in three
nucleated-patch experiments using TTX. The currents evoked by 2 and 5 msec current pulses are shown on an expanded time scale in Figure
2. In all cases in which it was tested,
0.5 µM TTX completely blocked the currents evoked by a 20 Hz train of depolarizations (n = 3) (Fig.
2A). In response to 5 msec pulses, inactivation of
INa had a time constant of 0.78 ± 0.10 msec (n = 10), and almost complete inactivation
occurred by the end of the pulse (89 ± 3%; n = 10). Most experiments were performed using 2 msec depolarizations, and
inactivation was almost complete during these brief depolarizations as
well. At 20 Hz, however, recovery from inactivation was not complete
after the 48 msec interpulse interval; on average, the amplitude of the second response was only 80% of the first response (Table
1). This remaining, prolonged form of
inactivation accumulated with additional depolarizations, but complete
inactivation of INa never occurred (Fig.
1A,C). During repetitive 20 Hz depolarizations (15-20 pulses of 50-70 mV), INa achieved a
steady state that was on average 58% of the first response (Table 1).
Fast inactivation appeared to be unaffected by the prolonged
inactivation, because there was no significant difference between the
inactivation time constants of the first and last responses in a train
(paired-sample t test; n = 10;
p > 0.19). This can be seen by the superimposition of
the first response and a scaled version of the last response (Fig.
2B,D).
Fig. 2.
Na+ currents in nucleated
patches inactivate rapidly and are blocked by TTX. A,
Voltage-gated Na+ currents evoked by 50 mV, 5 msec
depolarizations. Command potentials are shown above the current
responses. The first (large) and fifteenth (small) responses in a train
of step depolarizations (20 Hz) are superimposed, revealing the current
reduction attributable to cumulative, prolonged inactivation. The
response in the presence of 0.5 µM TTX is also
superimposed. Imperfect capacitive transient subtraction is apparent at
the beginning and end of the responses. Each current trace is an
average of 24 trials. B, The same data as in
A, but with the fifteenth response scaled (dotted
line) to match the peak amplitude of the first response,
revealing the similar time course of fast inactivation.
C, Similar data as in A, but from a
different nucleated patch, and in response to 50 mV, 2 msec
depolarizations. Each current trace is an average of six trials.
D, Data in C, with the fifteenth response
scaled (dotted line) to match the peak amplitude of the
first response.
[View Larger Version of this Image (16K GIF file)]
Table 1.
Properties of prolonged sodium channel inactivation in
somatic and dendritic patches
|
20 Hz
Train
|
Recovery
|
| Second pulse |
Last pulse |
200
msec |
500 msec |
1000 msec |
2000 msec |
|
| % of first
pulse |
| Soma |
80 ± 1 |
58 ± 2 |
66
± 4 |
72 ± 2 |
77 ± 2 |
86 ± 4 |
|
n
= 30 |
n = 30 |
n = 13 |
n
= 17 |
n = 14 |
n = 8
|
| Dendrite |
85 ± 2 |
44 ± 5 |
60 ± 0 |
63
± 6 |
82 ± 1 |
76 ± 7 |
|
n
= 8 |
n = 8 |
n = 2 |
n
= 4 |
n = 2 |
n = 2 |
| % Inactivation
|
| Soma |
20 ± 1 |
42 ± 2 |
34 ± 4 |
28
± 2 |
23 ± 2 |
14 ± 4 |
| Dendrite |
15 ± 2 |
56
± 5 |
40 ± 0 |
37 ± 6 |
18 ± 1 |
24 ± 7 |
| %
Recovery |
| Soma |
|
|
16 ± 5 |
33 ± 3 |
50
± 3 |
72 ± 6 |
| Dendrite |
|
|
24 ± 1 |
35
± 2 |
63 ± 3 |
61 ± 7 |
|
|
Statistics were calculated from peak sodium current amplitudes
during 20 Hz trains of 2 msec step depolarizations and from test
depolarizations at various times after the train (e.g., Figs. 1A, 3A,B, 4). The values of the second
and last pulse responses during the train were computed as percentages
of the first response (second × 100/first or last × 100/first), or as the percentage inactivation [(first second) × 100/first or (first last) × 100/first]. Recovery was
computed as the percentage of the first response at the indicated time
after the train (recovery × 100/first), as the percentage of
current that remained inactivated [(first recovery) × 100/first], or as the percent of inactivated current that had
recovered [(recovery last) × 100/(first last)].
Values are mean ± SEM, and n is the total number of
patches, which are the same for the second and third pairs as for the
first pair of rows. Paired-sample t tests indicated that
responses to the second and last responses were significantly smaller
than the first response, for both somatic and dendritic patches
(p < 0.007).
|
|
Although the inactivation of INa occurred
rapidly (50% of the total inactivation was reached after the first 2 msec pulse), recovery from this form of inactivation was extremely
slow, with only 72% recovery occurring after 2 sec (Fig.
3A, Table 1), but could be
accelerated by hyperpolarization during the recovery period (Fig.
3B). The time course and voltage dependence of the recovery
from prolonged inactivation are similar to that of the recovery of
back-propagating action potential amplitude (Spruston et al.,
1995).
Fig. 3.
Na+ current recovers slowly but
is accelerated by hyperpolarization. A,
Na+ currents in a nucleated patch (three
superimposed responses, below the three command potentials) recover
very slowly from cumulative, prolonged inactivation. Test responses
200, 1000, and 2000 msec after the initial 20 Hz train of 50 mV, 2 msec
depolarizations exhibit 20, 40, and 65% recovery, respectively, of the
inactivated portion of the current. Each current trace is an average of
three to four trials. B, In a different nucleated patch,
recovery is accelerated by a 30 mV hyperpolarization during the 500 msec recovery period. Recovery is 49% in control (left)
and 96% with hyperpolarization (right). Each current
trace is an average of three trials.
[View Larger Version of this Image (31K GIF file)]
The rationale for studying the inactivation properties in nucleated
patches was to take advantage of the large currents that can be
obtained in this recording configuration. Because sodium channels have
been shown to be similar in the soma and dendrites of CA1 pyramidal
neurons (Magee and Johnston, 1995), it seems reasonable to make
inferences about how the properties of somatic INa will affect action potential propagation in
dendrites. To determine whether dendritic INa
has the same inactivation properties as somatic
INa, however, we performed experiments on
INa in cell-attached dendritic patches. As
expected from the relative patch size, currents in dendrite-attached
patches were substantially smaller than in nucleated patches, but
cumulative, prolonged inactivation of INa was
still observed (Fig. 4). On average, the
steady-state INa in dendritic patches was 44%
of the initial current amplitude (n = 8; 28-240 µm
from the soma) (Table 1), which was significantly greater than the
attenuation observed in somatic patches (two-sample t test;
p < 0.006). These results also obviate any concern
that the prolonged inactivation of INa might be
an artifact of the cytoplasmic dialysis that occurs during
nucleated-patch recording.
Fig. 4.
Na+ currents in
dendrite-attached patches also exhibit cumulative, prolonged
inactivation. A, Na+ currents in a
dendrite-attached patch (203 µm from the soma) evoked by a 20 Hz
train of 50 mV, 2 msec depolarizations. Steady-state current is 20% of
the first response and 38% of the inactivated current recovered after
500 msec. The current trace is an average of 13 trials. Recording was
performed at 35°C. B, The first and last responses in
the train shown in A are superimposed and displayed on
an expanded time scale.
[View Larger Version of this Image (18K GIF file)]
The second hypothesis, that activity-dependent action potential
back-propagation could be caused by a shunt developing in the
dendrites, was tested in two ways. First, the response to a small
hyperpolarizing current pulse was compared before and after a train of
action potentials. Second, EPSP amplitude was compared before and after
a train of action potentials. If a shunt capable of influencing action
potential back-propagation develops as action potentials activate
dendritic conductances, it should manifest itself as a decrease in the
response to a hyperpolarizing current pulse and/or a decrease in EPSP
amplitude after a train of action potentials. Furthermore, the shunt
should be detectable hundreds of milliseconds after the train, when
dendritic action potentials remain attenuated (Spruston et al., 1995).
Figure 5 shows that no such decrease in
the voltage response to a small hyperpolarizing current pulse is
observed. The test response began 50 msec after the end of the
depolarizing current pulse evoking the train, and the steady-state
amplitude was measured 225-250 msec after the train (with the slow
afterhyperpolarization subtracted) (see Fig. 5 legend). The development
of a shunt would be expected to produce a significant reduction in the
size of the test response. We reasoned that this change might be
largest in the dendrites, where the shunt ought to develop if it were
to affect action potential back-propagation, so the experiment was
performed in dendritic recordings. In contrast to the prediction of a
shunt, the test responses were almost identical in amplitude to the
control responses (test/control = 1.01 ± 0.06 after 15-25
action potentials; n = 7 dendritic recordings 56-210
µm from the soma). One complicating factor in the interpretation of
this experiment is the sag in the voltage response, mediated by the
hyperpolarization-activated conductance Ih. An
increase in this conductance (e.g., after Ca2+
elevation during the train) (Hagiwara and Irisawa, 1989) could produce
a shunt that is masked by its own tendency to reduce the steady-state
response to a hyperpolarizing current pulse. To test this possibility,
we also monitored hyperpolarizing responses before and after a train in
the presence of 5 mM CsCl to block Ih. Under these conditions we still found no
evidence for a shunt (test/control = 0.98 ± 0.04 after
15-35 action potentials; n = 3 dendritic recordings
56-196 µm from the soma; data not shown).
Fig. 5.
Small hyperpolarizing current injections in the
dendrites do not reveal a global shunt after a train of action
potentials. A, Single trace response
(top) showing the effect of a train of 33 action
potentials in 1 sec on the response to a small hyperpolarizing current
pulse (bottom; hyperpolarizing current injections are 10 pA and depolarizing current injection is 400 pA). Apical dendritic recording is 168 µm from the soma. B, Average of eight
responses like the one in A. C, Enlarged
view of the average control hyperpolarization before the train of
action potentials. D, Enlarged view of the average test
hyperpolarization after the train of action potentials. The
afterhyperpolarization measured in the absence of a test pulse was
subtracted from the response with the test pulse.
[View Larger Version of this Image (25K GIF file)]
The prediction that a dendritic shunt would produce a reduction of EPSP
amplitude was also tested experimentally. EPSPs were evoked by
stimulation in distal stratum radiatum or in stratum lacunosum/moleculare and monitored in somatic recordings. This experiment should maximize the likelihood of detecting a shunt, by
virtue of the fact that EPSPs generated in the distal apical dendrites
must travel a long distance to the soma and could be affected by a
shunt anywhere along the way. Nevertheless, we found no evidence for a
shunt. EPSPs varied in amplitude from trial to trial; in some cases the
test EPSP was larger than control and in some cases it was smaller, but
the average change in EPSP amplitude was insignificant (Fig.
6A) (test/control = 1.06 ± 0.05; n = 6). To ensure that the
amplitude of the test EPSP was not affected by paired-pulse
facilitation or depression independent of the train of action
potentials, control experiments were performed with only a subthreshold
depolarization between the two synaptic responses (Fig.
6B). In these experiments the control and test EPSP
amplitudes were also similar (test/control = 1.06 ± 0.07; n = 6). The test/control EPSP ratio observed with a
train of action potentials was not significantly different from the
ratio with a subthreshold depolarization (paired-sample t
test; n = 6; p > 0.9), suggesting that
the train of action potentials does not produce a global dendritic
shunt.
Fig. 6.
Somatically recorded EPSPs also do not reveal a
global shunt after a train of action potentials. A,
Average of 12 EPSPs before and after +180 pA current injections evoking
trains of 16 action potentials on average (a).
The control EPSP (b) and test EPSP after the
train (c) have similar amplitudes. The
afterhyperpolarization measured in the absence of a test EPSP has been
subtracted from the test EPSP (c).
B, Average of 11 EPSPs before and after subthreshold depolarizations evoked by a +120 pA current pulse
(a). The control EPSP (b)
and test EPSP (c) have amplitudes similar to one
another and to those shown in A. The dashed
lines are drawn at the same levels (relative to baseline) in
A and B.
[View Larger Version of this Image (23K GIF file)]
Two other possible mechanisms underlying activity-dependent attenuation
of back-propagating action potentials were also tested: (1) that
attenuation is related to voltage-gated Ca2+ current
inactivation and (2) that attenuation is caused by a shunt induced by
recurrent synaptic activation. These mechanisms we regarded as unlikely
albeit formal possibilities. Both hypotheses can be excluded by the
experiment shown in Figure 7. Application of CdCl2 at a concentration sufficient to block
high-threshold Ca2+ channels (200 µM)
did not prevent action potential attenuation in dendritic recordings
(n = 6). In one recording, 50 µM
NiCl2 was coapplied to block low-threshold
Ca2+ channels as well, and still no effect was
observed on action potential attenuation (Fig. 7). Although the firing
pattern sometimes changed slightly in the presence of these blockers
(perhaps because of effects on Ca2+-activated
K+ channels), activity-dependent back-propagation
always persisted, indicating that neither high-threshold voltage-gated
Ca2+ channels nor Ca2+-activated
K+ channels are required for activity-induced
changes in the ability of action potentials to invade CA1 dendrites.
Blocking Ca2+ channels also completely blocked
synaptic transmission (Fig. 7), thereby ruling out the possibility that
action potential attenuation is mediated by recurrent synaptic activity
(e.g., attributable to a shunt induced by recurrent inhibition).
Similar observations were made using blockers of synaptic transmission,
such as D-AP5, CNQX, and bicuculline (n = 4).
Fig. 7.
Blocking voltage-gated Ca2+
channels with CdCl2 and NiCl2 does not prevent
activity-dependent spike attenuation in dendrites. A,
Action potentials evoked by a +400 pA current injection in an apical
dendritic recording 174 µm from the soma exhibit activity-dependent attenuation. Synaptic responses evoked before and after the train of
action potentials were used to monitor the effects of CdCl2 and NiCl2 in B. B,
Activity-dependent action potential attenuation is not affected by the
application of 200 µM CdCl2 and 50 µM NiCl2 to block high- and low-threshold
calcium channels, respectively. The effectiveness of these blockers is
indicated by the elimination of the synaptic responses before and after
the train (only stimulus artifacts are visible).
[View Larger Version of this Image (18K GIF file)]
DISCUSSION
Our results suggest that the activity-dependent attenuation of
action potentials that occurs as spikes back-propagate into the
dendrites of CA1 pyramidal neurons is mediated by a cumulative, prolonged form of Na+ channel inactivation. Action
potentials are initiated in the axon of CA1 cells, probably in the
first node of Ranvier (Colbert and Johnston, 1996a). Initiation is
likely to occur at this site because of a high density of
Na+ channels there compared with the somatic and
dendritic membrane (Mainen et al., 1995; Rapp et al., 1996). As action
potentials invade the soma and dendrites, they encounter a lower
density of Na+ channels, which is sufficient to
support active back-propagation, but with significant attenuation of
action potential amplitude as a function of distance from the soma
(Spruston et al., 1995). The data presented here indicate that as the
first action potential in a train invades the dendrites, a fraction of
the dendritic Na+ channels becomes inactivated. At
typical firing rates for CA1 pyramidal neurons (e.g., 20 Hz), the
interspike interval is too short for complete recovery to occur from
the prolonged form of inactivation, so the next spike will encounter an
even lower density of available Na+ channels, and
hence this spike will attenuate more than the first spike as it
propagates along the dendrite. Axonal action potentials are unlikely to
be affected by prolonged Na+ channel inactivation,
however, because it is never complete, and the density of
Na+ channels in the axon is likely to be so high
that it is not significantly affected by the ~40% inactivation at
steady state.
"Slow" inactivation of Na+ channels has been
described previously in several neuronal preparations (Narahashi, 1964;
Adelman and Palti, 1969; Chandler and Meves, 1970; Schauf et al., 1976; Rudy, 1978, 1981; Belluzi and Sacchi, 1986; Ogata et al., 1990; Ruben
et al., 1992; Colbert and Johnston, 1996b; Fleidervish et al., 1996).
In some cases the rates of both inactivation and recovery are
comparably slow, whereas in other cases, as we describe here, entry
into the slow inactivated state is faster than recovery from this
state. Slow inactivation has been proposed to account for slow
adaptation of action potential firing in Myxicola axons (Rudy, 1981) and in neocortical pyramidal neurons (Fleidervish et al.,
1996). This adaptation requires inactivation of sodium currents after
several seconds of depolarization, whereas the molecular mechanism
underlying activity-dependent action potential back-propagation must
occur more rapidly, because back-propagating action potential failure
can occur after even a single action potential (Spruston et al., 1995).
The inactivation we describe here has this important property, and we
therefore refer to this inactivation as "prolonged" rather than
"slow." It is nevertheless possible that the rapidly induced yet
prolonged inactivation we describe here is functionally similar to the
slow inactivation described by others. For example, although
Fleidervish and colleagues (1996) found that 200 msec depolarizations
produced an amount of inactivation similar to what we observed with
only 2 msec depolarizations, Rudy reports that in Myxicola
axons, long depolarizations are no more effective than much shorter
depolarizations at producing slow inactivation, presumably because the
slow inactivated state is primarily entered from the open state (Rudy,
1981). In agreement with our data, Rudy showed that sodium channels
accumulate in the slow inactivated state only if repetitive
depolarizations are applied (Rudy, 1981).
Our data suggest some interesting gating properties of
Na+ channels in CA1 neurons. A gating scheme that
can explain the salient features of the prolonged inactivation we
describe is presented in Figure 8. The
model has four states: closed (C), open
(O), inactivated (I), and prolonged
inactivated (PI). In developing the model, we focused
on the observation that cumulative inactivation of
INa occurs rapidly and reaches a substantial
steady state during repetitive brief depolarizations (Figs. 1, 3, 4),
despite the fact that recovery from the inactivated state is much
slower than the rate at which the inactivated state is reached. These
observations are surprising and require some special considerations.
Simpler models, in which entry into the PI state is proportional to the number of channels that open during a pulse (i.e., the O
PI
transition is prominent) and the recovery (PIC) is proportional to
the number of channels already in the PI state, predict either a
smaller steady-state INa or a faster recovery
from prolonged inactivation. A key feature of the gating scheme shown
in Figure 8 is that the total amount of prolonged inactivation during
repetitive depolarizations is limited by the fact that depolarization
promotes the PII transition and repolarization promotes the IC
transition. The PII transition is therefore central to the model;
without it, more Na+ channels would accumulate in
the PI state and smaller currents would be observed during repetitive
depolarizations. The model also explains the acceleration of recovery
by hyperpolarization, by promoting the PIC transition. Hence, our
data are consistent with a model of prolonged inactivation whereby
recovery from this state is promoted by both hyperpolarization
and depolarization. Although we emphasize that this model is
preliminary and cannot explain all of the available data in the
literature on Na+ channel gating, it demonstrates
some interesting features that more complete models should take into
account.
Fig. 8.
Model of a Na+ channel gating
scheme consistent with the properties of prolonged inactivation in
hippocampal CA1 pyramidal neurons. The states are closed
(C), open (O), inactivated
(I), and prolonged inactivated
(PI). Transitions promoted by depolarization move
upward, and transitions promoted by hyperpolarization move downward.
See Discussion for details.
[View Larger Version of this Image (11K GIF file)]
An alternative to such a complex gating scheme, however, is that
multiple populations of channels may exist, some that undergo prolonged
inactivation and others that do not. Such distinct subpopulations of
Na+ channels could arise because of different 
subunits, accessory subunits, or post-translational modifications
(possibly differentially distributed or susceptible to
neuromodulation). Distinguishing between these possibilities will
require additional experiments. Understanding whether the prolonged
inactivation properties of INa are determined by
one population or multiple populations of Na+
channels will also help to elucidate the mechanisms underlying the
difference in the prolonged inactivation of somatic and dendritic INa. One possibility is that the increased
prolonged inactivation of dendritic INa is
caused by differential post-translational modification of the same gene
product found at the soma; alternatively, multiple gene products could
be differentially distributed along the somato-dendritic axis.
Prolonged Na+ channel inactivation has been shown to
produce attenuation of back-propagating action potentials in a
computational model (Migliore, 1996). The degree of inactivation used
in the model, however, is substantially greater than we observed, so it
remains to be determined whether Na+ channel
inactivation alone is sufficient to explain all observed features of
the back-propagation during trains of action potentials, including
complexities such as asymmetrical branch point failures (Spruston et
al., 1995). The model also showed that a dendritic shunt could be
responsible for activity-dependent attenuation of back-propagating
action potentials. We find no evidence for such a shunt, but a few
caveats should be noted regarding this interpretation. First, the
method we used relies on an ability to discern changes in input
conductance as a change in the response to a hyperpolarizing current
pulse or an EPSP. Although we would expect a shunt to be measurable by
these methods if it is sufficient to alter the nature of spike
back-propagation, we have not tested this explicitly with a
computational model. The fact that we cannot measure a shunt associated
with the slow afterhyperpolarization suggests that such shunt
conductances are small under our conditions, but it also indicates that
the sensitivity of our method is limited. Second, a shunt could be
activated at potentials reached during an action potential but could be
inactive at rest; such a mechanism was included in the computational
model mentioned previously (Migliore, 1996). Although this is
theoretically possible, it requires a very particular biophysical
mechanism (e.g., a strongly rectifying shunt conductance). Finally, we
cannot rule out the possibility that small, localized shunts could
affect back-propagation but might be difficult to measure in the whole
cell. For example, local hot spots of voltage-gated
K+ channels could theoretically mediate asymmetrical
propagation of action potentials into different regions of the
dendritic tree.
Our experiments examine the question of which mechanisms are
responsible for action potential back-propagation in the resting state
in vitro. In vivo, other considerations are likely to come into play. For example, shunting and hyperpolarization attributable to
inhibition have been shown to limit the back-propagation of action
potentials into CA1 dendrites (Tsubokawa and Ross, 1996). This may
provide a mechanism for selectively allowing back-propagating action
potentials to reach certain dendritic compartments, but not others,
under defined conditions of interneuron activity. Such a mechanism
might function to selectively promote or inhibit associative plasticity
in restricted sets of synaptic inputs onto CA1 dendrites. Determining
how spike back-propagation might be regulated by inhibition or
neuromodulation of Na+ channel inactivation will be
an important direction for future studies aimed at understanding the
complex process of synaptic integration in these and other neurons.
FOOTNOTES
Received May 1, 1997; revised June 20, 1997; accepted June 23, 1997.
This manuscript was supported by National Institutes of Health Grant
NS35180-01 and the Human Frontiers in Science Program. Nelson Spruston
is a Sloan Fellow. We thank Nace Golding and David Ferster for
discussion and comments on this manuscript, and Arnd Roth for modeling
our channel gating scheme.
T.M. and H.J. contributed equally to this project.
Correspondence should be addressed to Dr. Nelson Spruston, Department
of Neurobiology and Physiology, Northwestern University, 2153 N. Campus
Drive, Evanston, IL 60208-3520.
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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;
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[Abstract]
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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]
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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):
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[Abstract]
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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]
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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):
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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):
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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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V. Sourdet and D. Debanne
The Role of Dendritic Filtering in Associative Long-Term Synaptic Plasticity
Learn. Mem.,
September 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;
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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):
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[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;
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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;
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[Abstract]
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A. Kamondi, L. Acsady, and G. Buzsaki
Dendritic Spikes Are Enhanced by Cooperative Network Activity in the Intact Hippocampus
J. Neurosci.,
May 15, 1998;
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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):
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[Abstract]
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H. Tsutsui and Y. Oka
Slow removal of Na+ channel inactivation underlies the temporal filtering property in the teleost thalamic neurons
J. Physiol.,
March 15, 2002;
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[Abstract]
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