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The Journal of Neuroscience, March 1, 2002, 22(5):1618-1628
Physiological Role of Calcium-Activated Potassium Currents in the
Rat Lateral Amygdala
E. S. Louise
Faber and
Pankaj
Sah
Division of Neuroscience, John Curtin School of Medical Research,
Australian National University, Canberra, ACT 2601, Australia
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ABSTRACT |
Principal neurons in the lateral nucleus of the amygdala (LA)
exhibit a continuum of firing properties in response to prolonged current injections ranging from those that accommodate fully to those
that fire repetitively. In most cells, trains of action potentials are
followed by a slow afterhyperpolarization (AHP) lasting several
seconds. Reducing calcium influx either by lowering concentrations of
extracellular calcium or by applying nickel abolished the AHP,
confirming it is mediated by calcium influx. Blockade of large
conductance calcium-activated potassium channel (BK) channels with
paxilline, iberiotoxin, or TEA revealed that BK channels are involved
in action potential repolarization but only make a small contribution
to the fast AHP that follows action potentials. The fast AHP was,
however, markedly reduced by low concentrations of 4-aminopyridine and
 -dendrotoxin, indicating the involvement of voltage-gated potassium
channels in the fast AHP. The medium AHP was blocked by apamin and
UCL1848, indicating it was mediated by small conductance
calcium-activated potassium channel (SK) channels. Blockade of these
channels had no effect on instantaneous firing. However, enhancement of
the SK-mediated current by 1-ethyl-2-benzimidazolinone or
paxilline increased the early interspike interval, showing that under
physiological conditions activation of SK channels is insufficient to
control firing frequency. The slow AHP, mediated by non-SK BK channels, was apamin-insensitive but was modulated by carbachol and
noradrenaline. Tetanic stimulation of cholinergic afferents to the LA
depressed the slow AHP and led to an increase in firing. These results
show that BK, SK, and non-BK SK-mediated calcium-activated potassium currents are present in principal LA neurons and play distinct physiological roles.
Key words:
AHP; BK channels; SK channels; apamin; paxilline; adaptation
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INTRODUCTION |
In many neurons, influx of calcium
during action potentials activates a number of potassium channels.
Activity of these channels generates currents that contribute to action
potential repolarization and the afterhyperpolarization (AHP) that
follows them (Lancaster and Pennefather, 1987 ; Storm, 1987; Sah and
McLachlan, 1992). Single-channel studies have identified two types of
calcium-activated potassium channel named BK and SK
channels. BK channels are large-conductance (200-400 pA),
voltage-sensitive channels that are selectively blocked by iberiotoxin
(Ibtx) (Galvez et al., 1990), low concentrations of tetraethylammonium
(TEA;  1 mM), and paxilline (Sanchez and McManus,
1996; Strobaek et al., 1996). SK channels have a smaller single-channel
conductance (10-20 pS), are voltage-insensitive and insensitive to low
concentrations of TEA, but are potently blocked by the bee toxin apamin
(Castle et al., 1989).
Macroscopically, three types of calcium-activated potassium current
have been described in central neurons that have been labeled
IC,
IAHP, and
sIAHP.
IC contributes to action potential repolarization and the fast AHP that follows single spikes (Lancaster and Adams, 1986; Lancaster and Nicoll, 1987; Storm, 1987; Sah and
McLachlan, 1992). IAHP and
sIAHP, which mediate the medium and slow AHPs, respectively, follow single and trains of action potentials (Storm, 1990; Sah, 1996). It is now clear that BK channels underlie IC, and activation of SK
channels generates IAHP (Sah, 1996). However,
although SK channels have also been suggested to underlie
sIAHP (Kohler et al., 1996;
Marrion and Tavalin, 1998; Bowden et al., 2001), the evidence for this
is not compelling. sIAHP is
apamin-insensitive, whereas all cloned SK channels are apamin-sensitive
when expressed in mammalian cell lines (Kohler et al., 1996; Shah and
Haylett, 2000). Furthermore,
sIAHP is modulated by a number
of neurotransmitters such as noradrenaline (Madison and Nicoll, 1982),
5-hydroxytryptamine (5-HT) (Pedarzani and Storm, 1993), acetylcholine
(Benardo and Prince, 1982; Cole and Nicoll, 1984), and histamine (Haas
and Konnerth, 1983), whereas such modulation has not been described for
the cloned SK channels. These results raise the possibility that the
channels underlying sIAHP may
represent an as yet unidentified type of calcium-activated potassium channel.
The amygdaloid complex is a structure located within the medial
temporal lobe that has been attributed with placing emotional significance to sensory input (LeDoux, 1995). Anatomically the amygdaloid complex can be divided into 13 nuclei, the main ones being
the lateral nucleus (LA), the basal nucleus (BLA), and the central
nucleus (Price et al., 1987; Pitkänen et al., 1997). Neurons
within the LA and BLA have been separated into two main types:
principal pyramidal-like cells, which are glutamatergic and form
projection neurons and local circuit interneurons, which are GABAergic
(McDonald, 1984). We have shown that spiny principal neurons within the
LA show a wide range of firing properties that form a continuum ranging
from those that show marked spike-frequency adaptation to those that
fire repetitively in response to a depolarizing current injection
(Faber et al., 2001). We have suggested that a combination of the
density and distribution of voltage-dependent and calcium-activated
potassium channels determine the firing properties of LA neurons. In
the current study we have examined the types of calcium-activated
potassium current present in LA principal neurons and their
physiological roles.
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MATERIALS AND METHODS |
All experiments were performed on rat brain slices maintained
in vitro. Wistar rats (unsexed; 17- to 28-d-old) were
anesthetized with intraperitoneal phenobarbitone (50 mg/kg) and killed
by decapitation. These procedures were in accordance with the
guidelines of the Institutional Animal Ethics Committee. Rat brains
were rapidly removed and placed in ice-cold artificial CSF
(aCSF) containing (mM): NaCl 118, KCl 2.5, NaHCO3, glucose 10, MgCl2
2.5, CaCl2 2.5, and NaHPO4
1.2. Coronal slices (400-µm-thick) containing the amygdala were cut
using a microslicer DTK-1000 (Dosaka). The slices were allowed to
recover in oxygenated (95% O2 and 5%
CO2) aCSF at 30°C for 30 min and then kept at
room temperature for a further 30 min before experiments were
performed. Slices were then transferred to the recording chamber as
required. Within the recording chamber slices were held in position
using a nylon net stretched over a flattened U-shaped platinum wire and
were continuously perfused with oxygenated aCSF maintained at 30°C. In experiments where the effect of a lower concentration of calcium was
examined, the composition of the aCSF was modified to contain 0.5 mM CaCl2. When using
cadmium to block voltage-gated Ca2+
channels, NaHPO4 was removed from the aCSF to
prevent cadmium from precipitating out of solution.
Whole-cell recordings were made from neurons in the LA using infrared
differential interference contrast techniques. Electrodes (3-6
M ) were filled with a pipette solution containing (mM): KMeSO4 135, NaCl 8, HEPES 10, Mg2ATP 2, and Na3GTP 0.3, pH 7.3 with KOH, osmolarity 280-300 mOsm/kg. Signals were recorded
using a patch-clamp amplifier (Axopatch 1-D; Axon instruments, Foster City, CA). Responses were filtered at 5 kHz and digitized at 10 kHz
(ITC-16; Instrutech, Great Neck, NY). All data were acquired, stored,
and analyzed on a Power Macintosh using Axograph (Axon Instruments).
To investigate the firing properties of neurons, six to eight current
injection steps (600 msec) were applied from  100 to +400 pA or +600
pA in 100 pA increments. Action potential half-widths were measured
using Axograph (Axon instruments) as the spike width at the
half-maximal voltage. The fast AHP immediately follows the downstroke
of the action potential (Fig. 2) and was measured by subtracting the
peak amplitude of the hyperpolarizing deflection after the spike from
the threshold for spike initiation. Medium and slow AHPs were evoked in
current clamp by a 50 msec, 400 pA current injection from a holding
potential of 70 mV. The currents underlying the medium and slow AHPs
were investigated in voltage clamp by giving a 100 msec, 50 mV step
from a holding potential of 50 mV (Fig.
1B). The medium AHP can
be distinguished from the slow AHP by its fast time course and
sensitivity to apamin: the medium AHP lasts several hundred
milliseconds, whereas slow AHP lasts up to 6 sec. The current
underlying the medium AHP, IAHP, was blocked using apamin
and examined by subtracting currents recorded in the presence of apamin
from control currents. For afferent stimulation, a bipolar stimulating
electrode was placed in the external capsule. Tetanic stimulation was
given as a 30 Hz stimulus lasting 500 msec, followed by a 5 sec delay
before giving either a depolarizing step in voltage clamp to evoke the AHP current or a depolarizing current injection in current clamp to
examine spike-frequency adaptation. This protocol was repeated four
times, twice without afferent stimulation to obtain control responses
of the AHP or firing properties and twice with afferent stimulation.
The protocol was then repeated again after the application of a drug if
appropriate. Drugs were applied by adding them to the superfusate at
the appropriate concentration. Complete exchange of solutions was
achieved within 2 min. Access resistance was 5-30 M and was
monitored throughout the experiment. Only cells with a membrane
potential greater than 55 mV were included in this study.
Instantaneous frequency was acquired by taking the inverse of the
interspike interval. Results are expressed as mean ± SEM.
Student's t tests were used for statistical comparisons between groups.
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Figure 1.
Electrophysiological properties of principal
neurons in the LA. A, Neurons in the LA show a continuum
of firing patterns ranging from full accommodation where they fire only
one to five spikes (A1) to firing repetitively
(A2) in response to a 400 pA, 600 msec current
injection. B, The current underlying the AHP is evoked
by a 100 msec, 50 mV step and can be separated into two components,
IAHP and
sIAHP. Cells that accommodate more
have a larger current underlying the slow AHP than those that fire
repetitively. B1 shows the current evoked in the cell
shown in A1, and B2 shows the current
evoked in the cell shown in A2.
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Drugs and chemicals. Ibtx, -dendrotoxin (DTX), and
apamin were obtained from Alomone Laboratories (Jerusalem, Israel);
nickel, cadmium, EGTA, BAPTA, carbachol, isoprenaline, paxilline,
tetraethylammonium (TEA), atropine, noradrenaline, dopamine,
5-hydroxytryptamine (5-HT), muscarine, and 4-aminopyridine (4-AP)
were obtained from Sigma (St. Louis, MO).
1S,3R-trans-ACPD and 1-ethyl-2-benzimidazolinone (EBIO) were obtained from Tocris Cookson (Bristol, UK). UCL1848 was a kind gift from Dr. Ganellin (University College, London, UK).
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RESULTS |
Two examples of principal neuron that form a continuum of firing
patterns in the LA (Faber et al., 2001) are shown in Figure 1. The
firing properties of LA neurons range from those that show spike-frequency adaptation (~80% of neurons) (Fig.
1A1) to those that fire repetitively in response to a
600 msec depolarizing current injection (~10%) (Fig.
1A2). Repetitively firing principal neurons are
clearly distinguishable from interneurons by their broader action
potential widths (Mahanty and Sah, 1998). Principal neurons also differ
from each other in the currents underlying the AHPs evoked by a 100 msec depolarizing step. Cells that accommodate have a significantly
(p < 0.05) larger
sIAHP than cells that do not
(Fig. 1B) (Faber et al., 2001). For ease we shall
refer to accommodating cells as AC and cells that fire repetitively as RFC. The other type of principal neuron that we have previously described (Faber et al., 2001), which fire a single spike in response to a 600 msec current injection and comprise ~10% of LA neurons, will not be included. A total of 261 LA neurons were recorded from with
a mean resting potential of 63.7 ± 0.4 mV and a mean input
resistance of 146.8 ± 4 M. Because of the relative proportions of AC and RFC, the majority of the experiments were performed on AC:
unless otherwise stated, the experiments were performed on AC.
BK-mediated currents
To test the role of BK channels, we first examined the effect of
blocking these channels on action potentials. BK channels can be
blocked by paxilline (Sanchez and McManus, 1996; Strobaek et al.,
1996), iberiotoxin (Galvez et al., 1990), and by low concentrations of
TEA. In 14 AC and 5 RFC, TEA (1 mM) caused a dramatic
(p < 0.001) broadening of the action potential
with the half-width increasing from a mean of 1.3 ± 0.1 to
2.0 ± 0.1 msec (n = 19) (Fig.
2A). Lower
concentrations of TEA (0.5 mM) had a similar effect (data not shown). Application of TEA reduced the fast AHP by
60% from 8.0 ± 1.5 to 5.5 ± 1.8 mV
(p < 0.005; n = 6). However, in
addition to blocking BK channels, TEA also blocks a number of
voltage-gated potassium channels (Coetzee et al., 1999). Therefore, we
next examined the effects of the more selective BK channel blockers
paxilline and Ibtx. In 13 AC and two RFC, paxilline (10 µM) significantly (p < 0.001) increased the mean spike half-width from 1.1 ± 0.04 to
1.4 ± 0.04 msec (Fig. 2B) (n = 15). Similarly, iberiotoxin (50 nM) also slowed
the repolarization of action potentials and increased the mean
half-width from 1.3 ± 0.1 to 1.7 ± 0.1 msec
(n = 9; p < 0.005) (six AC and three
RFC). In contrast to the actions of TEA, however, the fast AHP after
single spikes was little affected by paxilline (Fig.
2B) and iberiotoxin (data not shown); in paxilline it
was reduced from 9.8 ± 1 to 7.2 ± 1 mV, but this did not
reach statistical significance (n = 15; p > 0.05). Blockade of BK channels did not reduce the
slow AHP, although in some cells it was slightly enhanced, presumably
because of the larger influx of Ca2+
allowed by the broader spikes. This effect is not evident with paxilline in Figure 2C because the cell shown in the figure
is an RFC, in which the slow AHP is of very small
amplitude.
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Figure 2.
Currents mediated by BK channels are involved in
action potential repolarization in LA neurons, but contribute little to
the fast AHP. A, B, The effect of BK
channel blockers TEA (1 mM, A) and paxilline
(10 µM, B) on action potentials. The fast
AHP is indicated by the arrow. TEA both broadens the
spike (p < 0.001) and reduces the fast AHP
immediately after action potentials (p < 0.005). Paxilline has little effect on the fast AHP, but significantly
(p < 0.005) increased the spike half-width
(B). C, BK channels do not
contribute to the slow AHP. Neither TEA (1 mM,
left) nor paxilline (10 µM, right)
blocked the currents underlying the slow AHP. The increase in the
amplitude of sIAHP in the presence of
TEA is attributable to the large broadening of action poten tials and consequent increased calcium influx.
D, E, Two blockers of voltage-dependent
potassium currents 4-AP (C) and -dendrotoxin
(DTX, D) reduce the fast AHP that follows action
potentials without slowing action potential repolarization.
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The difference in the actions of TEA and paxilline on the fast AHP
suggests that a voltage-dependent current, other than that mediated by
BK channels, is the main contributor to the fast AHP. To test this
possibility we examined two other known blockers of voltage-gated
potassium channels. Application of 4-AP (30-50 µM)
significantly reduced the fast AHP to 53% of control values, from
11.4 ± 1.7 to 6.8 ± 2.1 mV (n = 7;
p < 0.005) (Fig. 2D). 4-AP (30-50
µM) had no effect on the spike half-width,
showing that it was not exerting its action through BK channels. The
mean half-width was 1.2 ± 0.1 msec both in control conditions and
in the presence of 4-AP (n = 7; p > 0.05) (Fig. 2D). Low concentrations of 4-AP blocks
potassium channels that are also blocked by the more selective
potassium channel blocker DTX (Coetzee et al., 1999). DTX (100 nM) also blocked the fast AHP by 60%
(p < 0.005) from 9.2 ± 1.2 to 6.2 ± 1.3 mV (n = 10) without increasing the spike half-width
(Fig. 2E). The mean spike half-width was 1.0 ± 0.1 msec in control compared with 1.1 ± 0.1 msec in DTX
(n = 13; p > 0.05). Together, these
findings indicate that in LA neurons the current mediating the fast AHP
is largely caused by activation of voltage-activated potassium channels
that are sensitive to 4-AP and DTX, whereas BK channels make a minimal contribution.
In hippocampal pyramidal neurons, trains of action potentials show a
frequency-dependent spike broadening, which has been attributed to fast
inactivation of BK channels (Shao et al., 1999). Principal neurons in
the LA also show a similar broadening of action potentials (Faber et
al., 2001). However, unlike in the hippocampus, this broadening was not
affected by TEA, paxilline, or iberiotoxin (data not shown), indicating
that it is unlikely to be attributable to inactivation of BK channels.
Currents underlying the medium and slow afterhyperpolarization
Our first aim was to ascertain whether the currents underlying the
AHP evoked by a depolarizing step (shown in Fig. 1) are calcium-activated currents. We first tested the effect of reducing calcium influx by either lowering extracellular
Ca2+ or by blocking voltage-activated
calcium currents with cadmium or nickel. Extracellular calcium was
reduced by replacing aCSF containing 2.5 mM
Ca2+ with 0.5 mM
Ca2+ containing aCSF. Lowering the
extracellular calcium concentration was associated with a dramatic
reduction of the AHP (Fig. 3A, left) (n = 6). Under voltage-clamp, the current
underlying the AHP (evoked by a 100 msec depolarization to 0 mV from a
holding potential of 50 mV) could be separated into two components.
One peaked shortly after the depolarizing voltage step and had a rapid decay ( , 86 ± 14 msec; n = 10; see below),
whereas the other was much slower to reach a peak and decayed with a
time constant of 1.4 ± 0.1 sec (n = 30). These
two components are similar to IAHP and
sIAHP described in other cells
(Fig. 1) (Sah, 1996). Both of these currents were abolished by reducing
extracellular calcium (Fig. 3A, right panel).
Blocking voltage-dependent calcium channels with cadmium (250 µM; n = 8) or nickel (5 mM; n = 6) (Fig. 3B)
also blocked the AHP and the underlying current. As a final test,
loading cells with the calcium chelator EGTA (10 mM) or BAPTA (10 mM) also
fully blocked the AHP and the underlying currents (Fig. 3C)
(n = 12). These results show that both components of
the AHP result from activation of calcium-activated potassium currents
secondary to calcium influx via voltage-gated calcium channels.
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Figure 3.
Activation of the AHP current requires calcium
influx and a rise in cytosolic calcium. A, The AHP
recorded under current clamp (left) and the underlying
current recorded in voltage clamp (right) were blocked
by perfusing slices with aCSF containing 0.5 mM
Ca2+. B, Blocking voltage-gated
calcium channels blocks the AHP (left traces, cadmium
0.25 mM) and the underlying current (right
traces, nickel 5 mM). C, Inclusion
of high concentrations of the calcium buffer EGTA (10 mM)
in the pipette solution abolished the AHP.
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SK channel-mediated currents
The SK channel blocker apamin (100 nM) (Castle et al.,
1989) had no effect on action potential width (Fig.
4A), but selectively and irreversibly blocked the medium AHP (Fig. 4B) and
IAHP (Fig. 4C) in 10 of 11 AC. The slow AHP and
sIAHP were unaffected by apamin
(Fig. 4B,C) (n = 15). Similarly to
apamin, UCL1848 (100 nM), another selective SK
channel blocker (Chen et al., 2000; Shah and Haylett, 2000), had no
effect on action potentials (data not shown) but selectively blocked
the medium AHP and IAHP (Fig. 4C, traces on right) (n = 4). The
currents mediated by SK channels were extracted by subtraction of the
current before and after application of apamin or UCL1848 and are shown
in the insets of Figure 4C. This current has a rapid time to
peak and decays with a time constant of 86 ± 14 msec
(n = 10). Bicuculline methiodide, which has been
reported to block SK channels (Johnson and Seutin, 1997) also
selectively blocked the medium AHP and
IAHP (n = 2; data not shown). Blockade of SK channels had no significant effect (p > 0.05) on accommodation in AC (Fig.
4D,E). The number of spikes fired (Fig.
4D) and the instantaneous firing frequency (Fig.
4E) were unaffected both at threshold and twice
threshold, with the mean number of spikes fired at twice threshold
being 4.2 ± 0.7 in control compared with 5.3 ± 1.1 in
apamin (n = 6; p > 0.05). UCL1848 also
had no significant effect on spike-frequency adaptation in terms of
either the number of spikes fired or the firing frequency (p > 0.05; data not shown).
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Figure 4.
Apamin-sensitive channels mediate the medium AHP
but play no role in spike-frequency adaptation. A,
Action potentials recorded in control aCSF and in the presence of
apamin (100 nM). Apamin had no effect
(p > 0.05) on the spike half-width.
B, The AHP evoked by a 100 msec depolarizing current
injection. In the presence of apamin, the medium AHP is blocked.
C, Left, Apamin blocks
IAHP but has no effect on the sIAHP. C,
Right, UCL1848 also blocks the
IAHP. The SK-mediated
IAHP obtained by subtraction is shown
in the insets. D, Train of action
potentials evoked by a 600 msec, 400 pA current injection. Apamin had
no effect on spike-frequency adaptation. The instantaneous firing
frequency during the spike train, and the lack of effect by apamin, is
shown in E.
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These results indicate that although apamin-sensitive SK channels are
present on LA neurons, they are not significantly activated by single
action potentials. One possible explanation for this is that the
calcium influx during action potentials does not raise calcium
concentrations near SK channels enough to significantly activate them.
As blockade of BK channels broadens the action potential, it is likely
that calcium influx would be potentiated (Jackson et al., 1991) and
thus might increase the activity of SK channels. In support of this,
application of paxilline increased the early interspike interval
(between spikes 1 and 2) by activating apamin-sensitive channels (Fig.
5A,B). Similar increases in
the early interspike interval between the first few spikes were also observed with TEA (data not shown). However, this change in the early interspike interval was not large enough to change the mean number of spikes evoked in AC at twice threshold current injections: 3.6 ± 0.4 in control versus 3.9 ± 0.9 in paxilline
(n = 13; p > 0.05); 2.9 ± 0.5 in
control versus 2.1 ± 0.4 in TEA (n = 14; p > 0.05); and 4.6 ± 0.8 versus 5.4 ± 1.2 in Ibtx (n = 7; p > 0.05).
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Figure 5.
Enhancement of the apamin-sensitive potassium
current increases the early interspike interval. Paxilline (10 µM) had no effect on spike-frequency adaptation
(A) but increased the early interspike interval
(B, right) by increasing the spike half-width (B,
left traces), mediated by enhanced calcium influx during the
spike. This effect on the interspike interval was reversed by apamin
(A, B, right traces).
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The benzimidazolinone EBIO has recently been reported to enhance the
calcium sensitivity of SK channels and to slow their decay after
activation by calcium (Pedarzani et al., 2001). Therefore we also
examined the effect of EBIO to confirm that the lack of effect of SK
channel blockers on firing was attributable to an inadequate activation
of SK channels in LA neurons. In agreement with Pedarzani et al.
(2001), loading cells with EBIO by including it in the internal pipette
solution (2 mM) (Fig.
6A), or adding EBIO
(0.5 mM) to the superfusate (data not shown),
slowed the decay of the apamin-sensitive current. The mean time
constant of decay in the presence of EBIO was significantly
(p < 0.001) enhanced from a mean of 86 ± 14 msec (n = 10) under control conditions to 227 ± 26 msec (n = 9) in EBIO. Application of EBIO also
enhanced the early interspike interval, an effect that was reversed by apamin (Fig. 6B,C).
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Figure 6.
EBIO slows the decay of
IAHP and increases the early
interspike interval. A, Inclusion of EBIO (2 mM) in the internal pipette solution slowed the decay of
the SK-mediated current. Currents underlying the AHP recorded in the
presence of EBIO and after application of 100 nM apamin
(left). The time courses of the apamin-sensitive
current, with and without EBIO (in different cells), have been
superimposed. B, C, Perfusion of EBIO
(0.5 mM) slows the interspike interval in an
apamin-sensitive manner.
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The slow AHP
In agreement with what has been reported in many other cells
types, the slow AHP that follows trains of action potentials was
insensitive to blockers of SK and BK channels (as shown above). One
distinguishing feature of the slow AHP is its modulation by a number of
neurotransmitters (Sah, 1996). In agreement with this, the slow AHP and
the underlying current were reduced by carbachol (20 µM;
n = 16), isoprenaline (10 µM;
n = 7), noradrenaline (10 µM;
n = 7), 5-HT (10 µM;
n = 7) and 1S,3R-trans-ACPD (100 µM; n = 2). The actions of
carbachol and noradrenaline are illustrated in Figure
7. In 8 of 16 cells inhibition of the
slow AHP by carbachol was associated with the generation of an
afterdepolarization (ADP). The effects of carbachol could be reversed
by the muscarinic antagonist atropine (1 µM;
n = 6) (Fig. 7A). Similarly, in two of seven
cells, blockade of the slow AHP by noradrenaline was also associated with the generation of an ADP.
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Figure 7.
Neurotransmitters modulate the slow AHP and reduce
spike-frequency adaptation. A1, Application of carbachol
(20 µM) depressed the slow AHP but not the medium AHP in
an atropine-sensitive manner. A2, This was accompanied
by a reduction in spike-frequency adaptation, which was reversed by
atropine (1 µM). B1, In the presence of
noradrenaline (10 µM), the slow AHP was blocked and was
replaced with a slow afterdepolarization. B2, In voltage
clamp, noradrenaline selectively blocked the
sIAHP, evoking an inward
current. B3, This caused a concurrent reduction in
accommodation. C, Similarly, 5-HT (10 µM)
selectively blocked the slow AHP (C1) and
sIAHP (C2), which caused a
decrease in spike-frequency adaptation (C3).
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Selective depression of the slow AHP by the neurotransmitters was
associated with a reduction in spike-frequency adaptation. In AC,
carbachol (20 µM) significantly reduced accommodation, increasing the number of spikes fired at the threshold depolarizing current injection from a mean of 2.6 ± 0.3 to 5.9 ± 0.8 (n = 16; p < 0.001) (Fig.
7A). These effects were reversed by atropine (n = 6). Similarly, isoprenaline (10 µM) also reduced (n = 7) spike-frequency adaptation. In AC, the mean number of spikes evoked increased from 2.9 ± 0.9 to 6.3 ± 0.9 after application of
isoprenaline (n = 7; p < 0.05). These
effects were reversible on washout. 5-HT (10 µM) also reversibly reduced accommodation in
five of seven neurons, increasing the number of evoked action
potentials from a mean of 1.7 ± 0.3 to 4.0 ± 0.9 at
threshold (n = 7; p < 0.05) (Fig.
7C). Similar blockade of the slow AHP and associated
increases in firing were seen with noradrenaline (10 µM; n = 7) (Fig.
7B), muscarine (10 µM;
n = 2) and 1S,3R-trans-ACPD (100 µM; n = 2).
Finally, to ascertain whether modulation of AHPs by neurotransmitters
and the concurrent changes in firing rates are physiologically relevant, we examined the effect of afferent stimulation on AHPs and
firing properties. The amygdala has a significant innervation by the
cholinergic system, the afferents of which travel in the external
capsule and can therefore be stimulated by placing a bipolar electrode
in the external capsule (Washburn and Moises, 1992). A train of stimuli
(30 Hz, 500 msec) to the external capsule caused a depression of the
slow AHP in all 11 neurons tested (Fig. 8A). This depression
was either reduced (n = 6) or prevented
(n = 1) by the application of muscarinic antagonist
atropine (1 µM) (Fig. 8B),
showing that the main neurotransmitter mediating the depression of the
AHP is acetylcholine acting at muscarinic receptors. As expected, the
reduction in the slow AHP was associated with a marked decrease in
spike-frequency adaptation (Fig. 9)
(n = 11).
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Figure 8.
Synaptic stimulation of cholinergic afferents
selectively depresses the slow IAHP.
A, Cholinergic afferents were stimulated at 30 Hz for
500 msec and followed by a 3 sec delay before evoking the
IAHP with a 100 msec voltage step.
After the tetanus, the slow IAHP was
depressed. B, Depression of the slow
IAHP by tetanic stimulation
(top traces) was reversed by atropine (1 µM; bottom traces), showing that the
reduction is caused by activation of muscarinic receptors.
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View larger version (20K):
[in this window]
[in a new window]
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Figure 9.
Tetanic stimulation evoked depression of the AHP
is accompanied by a reduction in spike-frequency adaptation.
Current-clamp recordings show that the AHP was depressed after tetanic
stimulation (indicated by an asterisk, top
trace), and this was accompanied by a reduction in
spike-frequency adaptation in response to a 600 msec, 400 pA current
injection (bottom traces).
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|
The above results show that in cells that accommodate fully, both
apamin-sensitive and apamin-insensitive calcium-activated potassium
channels are present. Spike-frequency adaptation is in the large part
determined by activation of the apamin-insensitive current. The
apamin-sensitive current contributes to a component of the AHP-evoked
during spike trains, but does not appear to play a major role in
setting the early interspike interval under physiological conditions.
We have shown previously that cells that show little spike-frequency
adaptation have a much smaller slow AHP (Faber et al., 2001). This
result suggests that the apamin-sensitive conductance may play a larger
role in controlling the early interspike interval in RFC. The effects
of blocking the apamin-sensitive and apamin-insensitive current in RFC
are shown in Figure 10. In four of four
cells, apamin blocked IAHP with
little effect on sIAHP (Fig.
10B). However, application of apamin had little
effect on the number of action potentials evoked by a twice threshold 200 pA, 600 msec current injection (Fig. 10A) and, as
with AC, had no effect on the instantaneous firing frequency (Fig.
10C). The mean number of spikes evoked by a threshold
current injection was and 4.0 ± 1.8 both under control and in the
presence of apamin (n = 4). Similar to AC, isoprenaline
(10 µM) selectively depressed the slow AHP and
slow IAHP in RFC (Fig.
10E). This led to an increase in the firing
rate at threshold from 2.5 ± 0.6 to 4.2 ± 0.5 spikes (n = 4; p > 0.05). However this
increase was not significant, which is not surprising in view of the
relatively smaller amplitude slow AHP present in RFC.
View larger version (24K):
[in this window]
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|
Figure 10.
Apamin-sensitive currents do not affect
spike-frequency adaptation in repetitively firing neurons.
A, Current-clamp recordings from a cell that showed
little spike-frequency adaptation. Apamin (100 nM) blocked
IAHP (B) but
had no significant effect (p > 0.05) on the
number of spikes evoked (A) or on the
instantaneous firing frequency (average data from four neurons;
C). D, Similarly to AC, isoprenaline (10 µM) increased the firing rate of RFC through blockade of
the slow IAHP
(E).
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DISCUSSION |
We have shown that three types of calcium-activated potassium
channel are present in principal LA neurons. These are BK channels, apamin-sensitive SK channels, and apamin-insensitive calcium-activated potassium channels. In neurons, these channels have been shown to
underlie three different calcium-activated potassium currents with
distinct functional roles. We find that in principal neurons of the LA
these channels also fulfill different physiological roles.
Activation of BK-type calcium-activated potassium channels underlies
the current IC which, in a
number of cell types, is well known to be involved in action potential
repolarization and the fast AHP that immediately follows it (Lancaster
and Nicoll, 1987; Storm, 1987; Sah and McLachlan, 1992). In LA
principal neurons, we found that BK channels also contribute to action
potential repolarization but have no effect on the slower AHP.
Surprisingly, however, blockade of BK channels had very little effect
on the fast AHP. In contrast, 4-AP and -dendrotoxin significantly
attenuated the fast AHP without broadening the action potential. We
have previously shown that LA neurons express a large dendrotoxin and 4-AP-sensitive current that shows rapid activation kinetics (Faber and
Sah, 2000). Our results indicate that this current is activated during
the action potential and contributes to the fast AHP. Dendrotoxin is a
selective voltage-gated potassium channel blocker that acts only on
channels that contain Kv.1, Kv1.2, or Kv1.6 subunits (Coetzee et al.,
1999). Low concentrations of 4-AP also block channels containing these
subunits (Coetzee et al., 1999). Thus, the channels that mediate the
fast AHP are likely to contain one or more of these subunits.
In adrenal chromaffin cells, blockade of BK channels and consequent
broadening of the action potential leads to a reduction in repetitive
activity (Solaro et al., 1995; Lovell and McCobb, 2001). This effect
has been attributed to a reduction in the entry of sodium and calcium
channels into desensitized states when BK channels are active and the
resulting hyperpolarization after the action potential. Similarly, in
amygdalar neurons we also noted that the early interspike interval was
longer when BK channels are blocked (Fig. 5). However, because the slow
AHP appears to be the major determinant of repetitive activity in these
cells, there was no change in the number of action potentials evoked by
current injections. In hippocampal pyramidal neurons the sodium current
has been shown to undergo prolonged inactivation during action
potentials. However, the effects of this inactivation are only seen in
the dendrites where sodium channel density is lower (Jung et al.,
1997). Thus, it is possible that recordings in dendrites of LA
pyramidal cells would also show more dramatic changes during blockade
of BK channels.
Similar to some other cell types, there is clear spike broadening
during action potential trains in LA neurons (Faber et al., 2001). In
hippocampal CA1 pyramidal neurons this phenomenon has been attributed
to rapid inactivation of BK channels during action potentials (Shao et
al., 1999). In contrast, we find that in LA neurons spike broadening is
unaffected after blockade of BK channels, indicating that it is likely
to be caused by a different mechanism (data not shown). BK channels are
composed of an subunit in heterologous combination  subunits. Four subunits, 1 (KCNMB1), 2(KCNMB2), 3(KCNMB3),
and 4 (KCNMB4) have so far been cloned (Dworetzky et al., 1994;
Knaus et al., 1994; Tseng-Crank et al., 1996; Brenner et al., 2000;
Meera et al., 2000). The presence of the subunit significantly
modifies the pharmacology, voltage dependence, and kinetics of the
assembled protein (McManus et al., 1995; Dworetsky et al., 1996;
Nimigean and Magleby, 1999; Wallner et al., 1999; Xia et al., 1999,
2000; Brenner et al., 2000). Channels containing the subunit in
isolation or in combination with the 1 or 4 subunits produce
sustained currents that do not inactivate. In contrast, the presence of
2 and 3 subunits gives rise to channels that show rapid
inactivation (Wallner et al., 1999; Xia et al., 1999, 2000; Brenner et
al., 2000; Uebele et al., 2000). Because BK channels involved in action
potential repolarization do not appear to inactivate between action
potentials, our results suggest that BK channels involved in spike
repolarization in LA neurons are likely have a different subunit
composition to those found in CA1 pyramidal neurons.
Apamin-sensitive channels in LA neurons are responsible for the rapidly
activating IAHP. As in other
cells, this current had no effect on action potential shape but
contributed to the medium AHP evoked by trains of action potentials in
cells at both ends of the firing pattern continuum. In other neurons
that express the apamin-sensitive
IAHP but have a very small or
absent apamin-insensitive slow AHP, depolarizing current injection
causes tonic firing of action potentials, with
IAHP being an important
determinant of the frequency of action potentials (Sah, 1996; Wolfart
et al., 2001). In some neurons where both currents are present (e.g., hippocampal CA1 pyramidal neurons), activation of
IAHP has been suggested to play
an important role in early spike-frequency adaptation, because the
predominant effect of SK channel blockers was to decrease the early
interspike interval (Stocker et al., 1999). In contrast, in LA
principal neurons apamin and UCL1848, which clearly blocked IAHP, had no effect on either
the number of spikes fired or on the early interspike interval.
However, enhancement of the SK channel mediated current by either
broadening the action potential with BK channel blockers or by altering
the calcium sensitivity of the channels with EBIO slowed the early
interspike interval as shown in hippocampal pyramidal neurons
(Pedarzani et al., 2001). This result suggests that the concentration
of calcium attained at SK channels during action potentials in the LA
is significantly lower than that seen by channels in the hippocampus.
This may be attributable to differences in localization of calcium
channels and SK channels in these neurons. Thus, apamin-sensitive
currents, although present in amygdalar principal neurons, do not
appear to play a role in controlling spike frequency under normal
conditions, and the exact physiological role of apamin-sensitive SK
channels in the LA remains elusive.
As in many other neurons a third calcium-activated current,
sIAHP, is also present in LA
principal neurons. This current has slow kinetics, is insensitive to
apamin, but is modulated by a number of neurotransmitters. As in
hippocampal (Madison and Nicoll, 1982) and BLA neurons (Womble and
Moises, 1993), this current is important in spike-frequency adaptation
in the LA. Control of excitability by the slow AHP is achieved by
hyperpolarization of the membrane, and thus prevention of the membrane
potential from reaching threshold for further spiking. As in CA1
hippocampal pyramidal neurons and in BLA neurons, the slow AHP is
greatly reduced after activation of cholinergic afferents. This
blockade of the slow AHP leads to a large reduction in spike-frequency adaptation. Thus neurotransmitter modulation of this conductance represents an important mechanism for modulating the output of LA neurons.
Although four types of SK channels have so far been cloned, SK1, SK2,
SK3, and SK4, only SK1-SK3 are found within the CNS (Stocker and
Pedarzani, 2000). It had been suggested that because SK1 is much less
apamin-sensitive than SK2 and SK3, the slow AHP may be mediated by SK1
channels (Vegara et al., 1998). SK1 transcripts do not appear to be
present in the LA (Stocker and Pedarzani, 2000), whereas the
apamin-insensitive slow AHP is seen in the vast majority (~90%) of
principal cells. Furthermore, the apamin insensitivity of SK1 has been
found to vary between expression systems, and these channels are
blocked by apamin when expressed in mammalian cells (Shah and Haylett,
2000; Strobaek et al., 2000). For these reasons we feel it is unlikely
that SK1 channels underlie the
sIAHP (Sah and Clements, 1999).
Unlike SK1, however, both SK2 and SK3 are present in the LA (Stocker
and Pedarzani, 2000), consistent with the presence of apamin-sensitive
currents in all principal cells from which we have recorded.
In conclusion, these findings show that BK, SK, and non-SK/BK-mediated
currents that comprise the AHP are present in almost all principal
neurons in the LA, ranging from those that show full spike-frequency
adaptation to those that do not. Although BK channels play an important
role in repolarizing the membrane after spike initiation, the slow AHP
plays a role in controlling the firing properties of these cells. The
role of the medium AHP is currently elusive. However, it is clear that
although the non-SK/BK-mediated calcium-activated potassium currents
control spike-frequency adaptation in LA neurons, this is not the only
factor that dictates the firing properties because blockade of the AHP
often does not lead to a complete inhibition of accommodation. This is
indicated by the inability of neurotransmitters to completely prevent
spike-frequency adaptation despite abolishing the slow AHP. The
mechanisms underlying this spike-frequency adaptation remain to be
elucidated in the future.
| |
FOOTNOTES |
Received Sept. 25, 2001; revised Dec. 10, 2001; accepted Dec. 13, 2001.
This work was supported by the John Curtin School of Medical Research.
We thank John Power, Mikel de Armentia, and Dennis Haylett for comments
on this manuscript.
Correspondence should be addressed to Dr. Pankaj Sah, The Division of
Neuroscience, The John Curtin School of Medical Research, GPO Box 334, Canberra, ACT 2601 Australia. E-mail: pankaj.sah{at}anu.edu.au.
| |
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E. S. L. Faber, A. J. Delaney, J. M. Power, P. L. Sedlak, J. W. Crane, and P. Sah
Modulation of SK Channel Trafficking by Beta Adrenoceptors Enhances Excitatory Synaptic Transmission and Plasticity in the Amygdala
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[Abstract]
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S. Iwasaki, Y. Chihara, Y. Komuta, K. Ito, and Y. Sahara
Low-Voltage-Activated Potassium Channels Underlie the Regulation of Intrinsic Firing Properties of Rat Vestibular Ganglion Cells
J Neurophysiol,
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[Abstract]
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R. Krahe, J. Bastian, and M. J. Chacron
Temporal Processing Across Multiple Topographic Maps in the Electrosensory System
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[Abstract]
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W. H. Mehaffey, L. Maler, and R. W. Turner
Intrinsic Frequency Tuning in ELL Pyramidal Cells Varies Across Electrosensory Maps
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J. M. Power and P. Sah
Competition between Calcium-Activated K+ Channels Determines Cholinergic Action on Firing Properties of Basolateral Amygdala Projection Neurons
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M. Teagarden, J. F. Atherton, M. D. Bevan, and C. J. Wilson
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R. Yamamoto, Y. Ueta, and N. Kato
Dopamine Induces a Slow Afterdepolarization in Lateral Amygdala Neurons
J Neurophysiol,
August 1, 2007;
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[Abstract]
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J. M. Power and P. Sah
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[Abstract]
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X.-H. Zeng, G. R. Benzinger, X.-M. Xia, and C. J. Lingle
BK Channels with {beta}3a Subunits Generate Use-Dependent Slow Afterhyperpolarizing Currents by an Inactivation-Coupled Mechanism
J. Neurosci.,
April 25, 2007;
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[Abstract]
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S. Duvarci and D. Pare
Glucocorticoids Enhance the Excitability of Principal Basolateral Amygdala Neurons
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M. Martina, M.-E. B. Turcotte, S. Halman, and R. Bergeron
The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus
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E. Likhtik, J. G. Pelletier, A. T. Popescu, and D. Pare
Identification of Basolateral Amygdala Projection Cells and Interneurons Using Extracellular Recordings
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J. A. Luther and S. J. Birren
Nerve Growth Factor Decreases Potassium Currents and Alters Repetitive Firing in Rat Sympathetic Neurons
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D. Wicher, J. Berlau, C. Walther, and A. Borst
Peptidergic Counter-Regulation of Ca2+- and Na+-Dependent K+ Currents Modulates the Shape of Action Potentials in Neurosecretory Insect Neurons
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A. Limon, C. Perez, R. Vega, and E. Soto
Ca2+-Activated K+-Current Density Is Correlated With Soma Size in Rat Vestibular-Afferent Neurons in Culture
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J. de Dios Navarro-Lopez, J. M. Delgado-Garcia, and J. Yajeya
Cooperative Glutamatergic and Cholinergic Mechanisms Generate Short-Term Modifications of Synaptic Effectiveness in Prepositus Hypoglossi Neurons
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J. F. Atherton and M. D. Bevan
Ionic Mechanisms Underlying Autonomous Action Potential Generation in the Somata and Dendrites of GABAergic Substantia Nigra Pars Reticulata Neurons In Vitro
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G. C. Tombaugh, W. B. Rowe, and G. M. Rose
The Slow Afterhyperpolarization in Hippocampal CA1 Neurons Covaries with Spatial Learning Ability in Aged Fisher 344 Rats
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Dopamine Modulates Excitability of Basolateral Amygdala Neurons In Vitro
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A. Fisahn, S. F. Heinemann, and C. J. McBain
The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurones
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L. C. Santarelli, J. Chen, S. H. Heinemann, and T. Hoshi
The {beta}1 Subunit Enhances Oxidative Regulation of Large-Conductance Calcium-activated K+ Channels
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September 27, 2004;
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C. Acuna-Goycolea and A. van den Pol
Glucagon-Like Peptide 1 Excites Hypocretin/Orexin Neurons by Direct and Indirect Mechanisms: Implications for Viscera-Mediated Arousal
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September 15, 2004;
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M. Ghamari-Langroudi and C. W. Bourque
Muscarinic Receptor Modulation of Slow Afterhyperpolarization and Phasic Firing in Rat Supraoptic Nucleus Neurons
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September 1, 2004;
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G. Martin, S. Puig, A. Pietrzykowski, P. Zadek, P. Emery, and S. Treistman
Somatic Localization of a Specific Large-Conductance Calcium-Activated Potassium Channel Subtype Controls Compartmentalized Ethanol Sensitivity in the Nucleus Accumbens
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July 21, 2004;
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J. de Dios Navarro-Lopez, J. C. Alvarado, J. Marquez-Ruiz, M. Escudero, J. M. Delgado-Garcia, and J. Yajeya
A Cholinergic Synaptically Triggered Event Participates in the Generation of Persistent Activity Necessary for Eye Fixation
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June 2, 2004;
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Q. Li, S. Guo-Ross, D. V. Lewis, D. Turner, A. M. White, W. A. Wilson, and H. S. Swartzwelder
Dietary Prenatal Choline Supplementation Alters Postnatal Hippocampal Structure and Function
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April 1, 2004;
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E. S. L. Faber and P. Sah
Opioids Inhibit Lateral Amygdala Pyramidal Neurons by Enhancing a Dendritic Potassium Current
J. Neurosci.,
March 24, 2004;
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A. S. Monaghan, D. C. H. Benton, P. K. Bahia, R. Hosseini, Y. A. Shah, D. G. Haylett, and G. W. J. Moss
The SK3 Subunit of Small Conductance Ca2+-activated K+ Channels Interacts with Both SK1 and SK2 Subunits in a Heterologous Expression System
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D. C H Benton, A. S Monaghan, R. Hosseini, P. K Bahia, D. G Haylett, and G. W J Moss
Small conductance Ca2+-activated K+ channels formed by the expression of rat SK1 and SK2 genes in HEK 293 cells
J. Physiol.,
November 15, 2003;
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[Abstract]
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E S L. Faber and P. Sah
Ca2+-activated K+ (BK) channel inactivation contributes to spike broadening during repetitive firing in the rat lateral amygdala
J. Physiol.,
October 15, 2003;
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N. E. Hallworth, C. J. Wilson, and M. D. Bevan
Apamin-Sensitive Small Conductance Calcium-Activated Potassium Channels, through their Selective Coupling to Voltage-Gated Calcium Channels, Are Critical Determinants of the Precision, Pace, and Pattern of Action Potential Generation in Rat Subthalamic Nucleus Neurons In Vitro
J. Neurosci.,
August 20, 2003;
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P. SAH, E. S. L. FABER, M. LOPEZ DE ARMENTIA, and J. POWER
The Amygdaloid Complex: Anatomy and Physiology
Physiol Rev,
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E. S. L. Faber and P. Sah
Calcium-Activated Potassium Channels: Multiple Contributions to Neuronal Function
Neuroscientist,
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[Abstract]
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J. R Edgerton and P. H Reinhart
Distinct contributions of small and large conductance Ca2+-activated K+ channels to rat Purkinje neuron function
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April 1, 2003;
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[Abstract]
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C. A. Sailer, H. Hu, W. A. Kaufmann, M. Trieb, C. Schwarzer, J. F. Storm, and H.-G. Knaus
Regional Differences in Distribution and Functional Expression of Small-Conductance Ca2+-Activated K+ Channels in Rat Brain
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November 15, 2002;
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TOP
ABSTRACT
INTRODUCTION
