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The Journal of Neuroscience, December 1, 2002, 22(23):10163-10171
Small Conductance Ca2+-Activated K+
Channels Modulate Synaptic Plasticity and Memory Encoding
Robert W.
Stackman2,
Rebecca S.
Hammond2,
Eftihia
Linardatos2,
Aaron
Gerlach1,
James
Maylie3,
John P.
Adelman1, and
Thanos
Tzounopoulos1, 2
1 Vollum Institute, Departments of
2 Behavioral Neuroscience and 3 Obstetrics and
Gynecology, Oregon Health and Science University, Portland, Oregon
97239-3098
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ABSTRACT |
Activity-dependent changes in neuronal excitability and synaptic
strength are thought to underlie memory encoding. In hippocampal CA1
neurons, small conductance Ca2+-activated
K+ (SK) channels contribute to the
afterhyperpolarization, affecting neuronal excitability. In the present
study, we examined the effect of apamin-sensitive SK channels on the
induction of hippocampal synaptic plasticity in response to a range of
stimulation frequencies. In addition, the role of apamin-sensitive SK
channels on hippocampal-dependent memory encoding and retention was
also tested. The results show that blocking SK channels with apamin
increased the excitability of hippocampal neurons and facilitated the
induction of synaptic plasticity by shifting the modification threshold
to lower frequencies. This facilitation was NMDA receptor (NMDAR)
dependent and appeared to be postsynaptic. Mice treated with apamin
demonstrated accelerated hippocampal-dependent spatial and nonspatial
memory encoding. They required fewer trials to learn the location of a
hidden platform in the Morris water maze and less time to encode object
memory in an object-recognition task compared with saline-treated mice. Apamin did not influence long-term retention of spatial or nonspatial memory. These data support a role for SK channels in the modulation of
hippocampal synaptic plasticity and hippocampal-dependent memory encoding.
Key words:
synaptic plasticity; Ca2+-activated
K+ channels; excitability; hippocampus; spatial
memory; object memory
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INTRODUCTION |
In hippocampal pyramidal neurons,
action potentials are followed by an afterhyperpolarization
(AHP) with three kinetic components. The predominant components,
the medium AHP (mAHP) and slow AHP (sAHP), are attributable
to the activation of small conductance Ca2+-activated
K+ (SK) channels (Blatz and Magleby, 1986 ;
Lancaster and Nicoll, 1987; Storm, 1990; Sah, 1996; Stocker et al.,
1999). In addition to their different kinetics, the mAHP and the sAHP
can be pharmacologically distinguished because apamin blocks the mAHP
but not the sAHP (Kohler et al., 1996; Sah and Clements,
1999; Stocker et al., 1999). Apamin, a peptide derived from
bee venom, is a highly selective blocker of SK channels, having no
other known targets (Garcia et al., 1991). In CA1 neurons, synaptic
activation may induce Ca2+ influx through
NMDA receptors (NMDARs) (Alford et al., 1993; Kovalchuk et al., 2000),
as well as through voltage-gated Ca2+
channels (Magee and Johnston, 1995). Synaptic activation of a Ca2+-dependent
K+ current resembling the
IsAHP reduces postsynaptic
excitability in response to high-frequency synaptic input (Lancaster et
al., 2001).
Multiple forms of synaptic plasticity occur at the Schaffer collateral
CA1 synapses, including long-term potentiation (LTP) and long-term
depression (LTD) (Malenka and Nicoll, 1993). Essential for these
processes is the influx of Ca2+ through
NMDARs and the consequent rise in cytosolic
Ca2+ (Lynch et al., 1983; Brocher et al.,
1992; Malenka et al., 1992; Mulkey and Malenka, 1992). The magnitude of
the rise in cytosolic Ca2+, as determined
by the degree and pattern of NMDAR activation, distinguishes whether a
synapse undergoes LTP or LTD. Trains of afferent stimuli capable of
inducing synaptic plasticity cause a summation of EPSPs that generate
action potentials. The consequent increases in intracellular
Ca2+ may activate SK channels; thus SK
channels may represent a mechanism for modulating the induction of
synaptic plasticity. Using a single stimulus frequency (100 Hz for 1 sec or 5 Hz for 3 min) (Behnisch and Reymann, 1998; Norris et al.,
1998; Foster, 1999), the magnitude of LTP induced in the CA1 region was
increased by extracellular application of apamin. The present
experiments investigated whether SK channels modulate the threshold for
synaptic plasticity as defined by the frequency-response function
(Bear, 1995) and the mechanism through which such a modulation may
occur. By using a wide range of stimulation frequencies, the results
show that SK channel activity modulated the threshold for the induction of synaptic plasticity through a postsynaptic mechanism that required NMDAR activation.
SK channel blockade has been shown to (1) facilitate
hippocampal-independent learning (Messier et al., 1991; Fournier et
al., 2001) and (2) enhance spatial memory in hippocampal-lesioned mice but not in intact mice (Ikonen et al., 1998; Ikonen and Riekkinen, 1999). Differences in behavioral paradigm and the precise memory process addressed complicate the literature concerning the cognitive effects of apamin in rodents. Based on our electrophysiological findings, hippocampal-dependent tests were specifically modified to
examine the effects of apamin on the initial stages of memory encoding.
The data demonstrate that apamin facilitated spatial and nonspatial
memory encoding in C57BL/6 mice.
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MATERIALS AND METHODS |
Electrophysiology
Hippocampal slices were prepared from 3- to 6-week-old male
C57BL/6NHsd mice (Harlan Sprague Dawley, Indianapolis, IN). Animals were anesthetized with halothane and decapitated. The cerebral hemispheres were quickly removed and placed in a partially frozen solution of artificial CSF (ACSF) (in mM): 119 NaCl, 2.5 KCl, 1.2 MgSO4, 2.5 CaCl2,
1 NaHPO4, 26.2 NaHCO3, and
10 glucose and equilibrated with 95% O2 and 5%
CO2. Hippocampi were removed, placed on an agar
block, and transferred to a slicing chamber containing a similarly
partially frozen solution. Transverse hippocampal slices (300-500 µm
thick) were cut with a Vibratome tissue slicer, transferred into a
humidified holding chamber, and allowed to recover for  1 hr before
recordings were performed. The following drugs were used: apamin
(Calbiochem, La Jolla, CA) and D-2
amino-5-phosphonovaleric acid (D-APV) (Tocris Cookson,
Ellisville, MO). Extracellular field potentials were recorded in the
stratum radiatum using electrodes (3-6 M ) filled with 3 M NaCl. For whole-cell recordings, CA1 pyramidal neurons
were visualized with a water-immersion objective (40×; Zeiss,
Thornwood, NY) using a microscope equipped with
infrared/differential interference contrast optics (Zeiss
Axioskop 2FS) and a CCD camera (Sony, Tokyo, Japan). Whole-cell
recording pipettes were fabricated from TW150F-4 thin-wall borosilicate
glass (World Precision Instruments, Sarasota, FL) and had resistances
of 1.5-3 M. Pipettes were filled with an intracellular solution
containing (in mM): 140 KMeSO4, 8 NaCl, 1 MgCl2, 10 HEPES, 2 Mg-ATP, 0.4 Na2-GTP, and 20 µM EGTA, pH 7.3, 290 mOsm. Slices were continuously perfused with ACSF. Whole-cell,
patch-clamp currents were recorded with an Axopatch 200A amplifier
(Axon Instruments, Foster City, CA), digitized using an ITC-16
analog-to-digital converter (InstruTech, Port Washington, NY), and
transferred to a computer using Pulse software (Heka Elektronik,
Lambrecht/Pfalz, Germany). CA1 neurons were voltage clamped at  55 mV,
and IAHP tail currents were evoked by
a depolarizing voltage command to +20 mV for 200 msec followed by a
return to 55 mV. Experiments on control slices were interleaved with
those on experimental slices. Data were collected and analyzed online
(10 kHz sampling rate) using IGOR (WaveTech, Lake Oswego, OR) and a
program kindly donated by Dr. Greg Hjelmstad (University of California
San Francisco, San Francisco, CA). The maximal initial slope of the
field EPSP was measured to monitor the strength of synaptic
transmission, minimizing contamination by voltage-dependent events.
Summary graphs were obtained by normalizing each experiment according
to the average value of all points on the 10 min baseline, aligning the
points with respect to the start of the (LTP and LTD) induction
protocol, dividing each experiment into 1 min bins, and averaging these
across experiments. The amount of potentiation or depression of the
synaptic response was measured 40-50 min after conditioning. Data are
expressed as mean ± SEM, as a percentage of the baseline.
Student's t test and two-factor ANOVA were used to
determine significance between groups of data; p < 0.05 was considered significant. Experiments were included in the data analysis only when LTP could be generated at the end of the
experimental manipulation, ensuring that the occurrence of short-term
potentiation or LTD was attributable to the experimental manipulation.
Morris water maze
To assess hippocampal-dependent spatial learning and memory,
naive male C57BL/6NHsd mice (4-6 weeks of age) were trained in a
Morris water maze (Silva et al., 1998; Cho et al., 1999). Before the
start of behavioral testing, mice were habituated over a 3 d
period to daily handling and intraperitoneal injection. Over the
following 2 d, all mice received nonspatial habituation trials (one trial per day). During these trials, a clear Plexiglas platform (13 cm diameter) was placed in the center of a white polyethylene pool
(60 cm high, 109 cm diameter), and floor-to-ceiling curtains were drawn
around the pool to block the animals' use of extra-maze cues. The
platform was 1 cm below the surface of the water, and the water was
rendered opaque by the addition of nontoxic white Tempra paint. Each
mouse was placed on the platform for 60 sec and then released into the
pool at four locations adjacent to the platform and allowed to swim and
climb onto the platform.
Spatial training. After nonspatial habituation, mice were
trained on the spatial (hippocampal-dependent) version of the water maze task. Training comprised 24 trials (four trials per day) during
which the platform remained submerged 1 cm below the water surface in a
fixed position in the center of one quadrant of the pool. During a
given trial, the mouse was introduced into the pool at one of four
possible start points (north, south, west, and east) and allowed 60 sec
to swim to the platform. The order of start points varied in a
pseudorandom manner for each mouse every day. After remaining on the
platform for 30 sec, the mouse was placed into a holding cage for a 45 sec intertrial interval. Throughout water maze testing, the water
temperature was maintained at 22-23°C. Each mouse received
intraperitoneal apamin (0.4 mg/kg, 10 ml/kg; Calbiochem) or 0.9%
saline (10 ml/kg) 30 min before the first training trial of each day.
This dose of apamin was defined in pilot studies conducted to determine
a dose that was behaviorally effective but that induced no motor or
convulsive effects.
Spatial memory testing. After the fourth, 12th, and 20th
training trials, a probe test was conducted in which each mouse
received a 30 sec free swim in the pool with the platform removed.
Twenty-four hours after the final training trial (24th trial), each
mouse received a 60 sec probe test of long-term retention. The behavior of the mice during training and probe tests was recorded with a
computerized video tracking system (EthoVision 2.2; Noldus, Leesburg,
VA) and analyzed to determine the amount of time spent in each of the
four quadrants of the water maze.
Object recognition
To assess the effects of apamin on nonspatial
hippocampal-dependent memory, naive male C57BL/6NHsd mice (4-6 weeks
of age) were tested in an object-recognition memory task (Vnek and
Rothblat, 1996; Clark et al., 2000). Before object recognition testing, all mice were habituated to intraperitoneal injection and to the open-field arena (38 × 38 × 64 cm high) for 5 min each day
for 3 d. During a subsequent sample session, two identical novel
objects [Duplo or Lego blocks (Lego Company, Billund, Denmark), toys, etc.] were placed into opposite corners (southwest and northeast) of
the open-field arena, and the mouse was allowed to explore the objects.
Pilot studies revealed that C57BL/6 mice averaged 38 sec of exploration
of either sample object during a 5 min sample session. For the present
study, the object recognition task was modified to explicitly examine
the influence of apamin on object memory encoding. To manipulate
encoding, mice were allowed to explore the sample objects until either
19 sec (minimal training) or 38 sec (extensive training) of object
exploration had been accumulated. Twenty-four hours after the sample
session, a test session was conducted during which each mouse was
placed back into the arena containing one of the familiar objects and a
novel object for 5 min. The spatial position of the novel object was counterbalanced so that one-half of the mice experienced the novel object in the southwest corner of the open field, whereas the other
half of the mice experienced the novel object in the northeast corner.
After each session, all objects were cleaned with 10% ethanol to
reduce the possibility that mice were imparting some odor cue to the
objects that would influence object exploratory behavior during a
subsequent test session. Pilot studies were conducted to select objects
that elicited equivalent degrees of exploration in mice. This is
necessary to verify that naive mice exhibited no inherent preference
for one object over the other.
The behavior of each mouse was recorded using the EthoVision system and
scored to determine the amount of time spent exploring each of the
objects during each session. Object exploration was defined as any time
that the mouse's head was oriented toward the object, was within 2-3
cm of the object, and its vibrissas were moving. Object recognition
memory was quantified by measuring the difference in exploration times
between the novel and familiar object. A novel object preference index,
a ratio of the amount of time spent exploring the novel object over the
total time spent exploring both objects, was used to measure
recognition memory. A novel object preference ratio of >0.5 indicates
that the mouse spent more time exploring the novel object than the
familiar one.
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RESULTS |
Apamin blocks SK channels underlying the mAHP and
increases excitability
CA1 neurons express an apamin-sensitive
ImAHP (Fig.
1A) thought to be
mediated by apamin-sensitive SK channels (Kohler et al., 1996; Stocker
et al., 1999). Action potentials recorded in response to current
injections showed that apamin (100 nM) increased the number of action potentials discharged in CA1 neurons (Fig. 1B). Control cells fired an average ± SEM of
4.7 ± 1.2 action potentials per depolarizing pulse (Fig.
1B1), which was increased to 6.7 ± 1.7 in the
presence of apamin (Fig. 1B2) (n = 5;
p = 0.04; paired Student's t test). This
result indicates that blockade of apamin-sensitive SK channels
increases excitability. Such changes in excitability may influence the
threshold for the induction of synaptic plasticity.
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Figure 1.
Blockade of the
apamin-sensitive afterhyperpolarization (mAHP) increases excitability.
A, IAHPs were evoked in the
whole-cell configuration by a 200 msec depolarizing pulse to +20 mV
followed by a return to the 55 mV holding potential.
IAHPs were obtained in the presence and
absence of apamin (100 nM). After application of apamin,
the medium-duration component (ImAHP)
of the tail current was selectively inhibited. Dashed line
indicates zero current. B, Apamin increased the number
of action potentials. B1, Response of a pyramidal neuron
to a 1 sec depolarizing current pulse. B2, Response of
the same neuron to the same depolarizing current pulse in the presence
of apamin (control cells fired an average ± SEM of 4.7 ± 1.2 action potentials/depolarizing pulse, which increased to 6.7 ± 1.7 with apamin; n = 5; p = 0.04; paired Student's t test).
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Blocking SK channels facilitates the induction of
synaptic plasticity
To investigate the role of SK channels on the induction of
synaptic plasticity at CA1 synapses, stimulation protocols that evoke
LTP or LTD were delivered to mouse hippocampal brain slices in the
presence or absence of apamin. Figure
2A shows the effect of
apamin (100 nM) application on the ability of
high-frequency stimulation (100 Hz applied twice for 1 sec, separated
by 10 sec) to generate LTP. Equal extents of LTP were observed in
control (164 ± 7%; n = 9 slices per 6 animals) and apamin-treated (165 ± 6%; n = 10 slices per 6 animals) slices, showing that apamin does not alter the
ability of high-frequency stimulation to induce robust LTP
(p > 0.05; unpaired Student's t
test). After a 50 Hz, 0.5 sec stimulus, significantly more LTP was
induced in the presence of apamin (125 ± 3%, n = 13 slices per 8 animals for apamin-treated slices; 106 ± 4%,
n = 12 slices per 8 animals for control slices; p < 0.05; unpaired Student's t test) (Fig.
2B). Using a 25 Hz, 0.5 sec stimulus, LTP was not
different in control and apamin-treated slices (120 ± 6%,
n = 8 slices per 6 animals for apamin-treated slices;
109 ± 9%, n = 8 slices per 6 animals for control
slices; p > 0.05; unpaired Student's t
test) (Fig. 2C).
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Figure 2.
Apamin block of SK channel activity
enhances plasticity induced by high-frequency stimulation.
A, A 100 Hz, 1 sec tetanus in control and apamin (100 nM)-treated slices (164 ± 7%,
n = 9 slices per 6 animals for controls; 165 ± 6%, n = 10 slices per 6 animals for apamin;
p > 0.05; unpaired Student's t
test). B, A 50 Hz, 0.5 sec stimulation protocol in
control and apamin (100 nM)-treated slices (106 ± 4%, n = 12 slices per 8 animals for control
slices, 125 ± 3%, n = 13 slices per 8 animals for apamin-treated slices; p < 0.05;
unpaired Student's t test). C, A 25 Hz,
0.5 sec stimulation protocol in control and apamin (100 nM)-treated slices (109 ± 9%, n = 8 slices per 6 animals for controls; 120 ± 6%,
n = 8 slices per 6 animals for apamin;
p > 0.05; unpaired Student's t
test). Control and apamin-treated slices were interleaved.
Synaptic strength was measured as the initial slope of the recorded
field EPSP. Dashed line indicates baseline response in
A-C.
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To determine whether apamin affects the threshold for induction of
synaptic plasticity, its effects on lower stimulation frequencies were
examined. A 10 Hz stimulation for 900 pulses resulted in LTD in control
slices (77 ± 6%; n = 10 slices per 6 animals), whereas apamin-treated slices did not show changes in synaptic strength
(101 ± 7%; n = 9 slices per 5 animals;
p < 0.05; unpaired Student's t test) (Fig.
3A). In addition, 5-Hz
stimulation for 900 pulses resulted in LTD in apamin-treated slices
(85 ± 5%; n = 9 slices per 5 animals) but did
not affect long-lasting changes in synaptic strength in control slices
(103 ± 4%; n = 10 slices per 6 animals;
p < 0.05; unpaired Student's t test) (Fig.
3B). These results suggest that apamin alters the
frequency-response relationship (Bear, 1995) for the induction of
synaptic plasticity. The modification threshold is the level of
postsynaptic response at which the sign of the synaptic modification
reverses from LTD to LTP (Bienenstock et al., 1982). The smooth
transition from LTD to LTP may be demonstrated by systematically
varying the frequency of conditioning stimulation for a given number of
pulses. The frequency-response relationships for control and
apamin-treated slices are presented in Figure 3C and
demonstrate that blockade of SK channels with apamin shifts the
frequency-response function to the lower frequencies, facilitating the
induction of synaptic plasticity.
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Figure 3.
Apamin block of SK channel activity
shifts the synaptic modification threshold to lower frequencies.
Induction of synaptic plasticity by 10 Hz, 900 pulse stimulation in
control slices (77 ± 6%; n = 10 slices per 6 animals) and apamin (100 nM)-treated slices (101 ± 7%; n = 9 slices per 5 animals;
p < 0.05; unpaired Student's t
test) (A) and 5 Hz, 900 pulse stimulation
protocol in control slices (103 ± 4%; n = 8 slices per 5 animals) and apamin (100 nM)-treated slices
(85 ± 5%; n = 9 slices per 5 animals;
p < 0.05; unpaired Student's t
test) (B). Dashed line indicates
baseline response. C, Frequency-response relationship
for the induction of LTP and LTD in controls and experiments from
slices in which apamin (100 nM) was applied. The mean
effect of 900 pulses of conditioning stimulation delivered at various
frequencies to the Shaffer collaterals on the synaptic response
measured 40-50 min after conditioning is shown.
*p < 0.05 versus respective control data point;
Student's t test. Dashed line indicates the
transition between LTD and LTP.
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Blocking SK channels does not affect neurotransmitter release
To investigate whether the apamin-induced shift in the
frequency-response function at CA1 synapses involves presynaptic or postsynaptic changes, the effects of apamin on paired-pulse
facilitation, post-tetanic potentiation, and short-term depression were investigated.
Paired-pulse facilitation, an increased second response to two stimuli
applied in rapid succession, is thought to reflect an increase in the
probability of neurotransmitter release (Katz and Miledi, 1968).
Paired-pulse facilitation was tested at interstimulus intervals ranging
from 20 to 100 msec and was not significantly altered by application of
apamin (p > 0.05; paired Student's
t test; n > 8 for all interstimulus
intervals) (Fig. 4A),
suggesting that apamin does not alter neurotransmitter release.
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Figure 4.
SK channels do not have presynaptic
effects in CA1. A, Paired-pulse facilitation
(PPF), measured as the ratio of the second
response to the first, was plotted as a function of interstimulus
interval for controls and in the presence of apamin
(n > 8 for all interstimulus intervals). No
significant differences were detected (p > 0.05; paired Student's t test). B, Time
course of post-tetanic potentiation elicited by 100 Hz, 1 sec tetanus
in control and apamin-treated slices. Post-tetanic potentiation (peak
enhancement in controls, 132 ± 6% of baseline,
n = 9 slices per 4 animals; peak enhancement in
apamin, 134 ± 5% of baseline, n = 9 slices
per 4 animals) was not different between groups
(p > 0.05; unpaired Student's
t test). C, Time course of short-term
depression elicited by 5 Hz, 900 pulse stimulation in control and
apamin-treated slices (80 ± 7% of baseline,
n = 6 slices per 3 animals; peak depression in
apamin, 82 ± 5% of baseline, n = 6 slices
per 3 animals). No significant differences were detected between groups
(p > 0.05; paired Student's
t test). Synaptic strength was measured as the initial
slope of the recorded field EPSP. Solid line in B
and C indicates the duration of D-APV
application.
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Post-tetanic potentiation, a slow decay of the postsynaptic responses
after repetitive stimulation has been terminated, presumably reflects
the slow decay of elevated presynaptic
Ca2+ levels induced by the tetanic
stimulus (Zucker, 1989). The effects of apamin on post-tetanic
potentiation were examined using a 100 Hz, 1 sec tetanus delivered in
the presence of D-APV (100 µM), an NMDA
receptor antagonist. The time course of post-tetanic potentiation was
not different between control and apamin-treated slices, nor were
differences detected in the peak enhancement achieved in the presence
or absence of apamin (control, 132 ± 6%, n = 9 slices per 4 animals; apamin treated, 134 ± 5%,
n = 9 slices per 5 animals; p > 0.05;
unpaired Student's t test) (Fig. 4B).
Short-term depression was also examined using a 5 Hz, 900 stimuli
tetanus delivered in the presence of D-APV (100 mM). This same protocol had revealed differences between
control and apamin-treated slices when performed in the absence of
D-APV (Fig. 3B). In the presence of
D-APV (Fig. 4C), the magnitude and
time course of depression were not different between control slices
(peak depression, 80 ± 7%, n = 9 slices per 4 animals) and apamin-treated slices (peak depression, 82 ± 5%,
n = 9 slices per 5 animals; p > 0.05; unpaired Student's t test). The lack of effect of apamin on
paired-pulse facilitation, post-tetanic potentiation, and short-term
depression suggests that apamin does not affect presynaptic events but
rather alters NMDAR-dependent postsynaptic events to shift the
threshold for the induction of synaptic plasticity in CA1 synapses.
Blocking SK channels accelerates hippocampal-dependent spatial
memory encoding
The results presented above indicate that apamin facilitates the
induction of synaptic plasticity in the CA1 region of the hippocampus.
It was hypothesized that apamin might also alter hippocampal-dependent
memory assessed in the Morris water maze, a task considered to require
the activation of NMDARs and synaptic plasticity in the hippocampus
(Morris et al., 1982; Tsien et al., 1996). Considering the finding that
apamin shifted the threshold for the induction of synaptic plasticity
(Fig. 3C), it was predicted that apamin would exert its
greatest influence during the initial stages of spatial memory
encoding. Specifically, the effects of systemic apamin were examined
using a version of the Morris water-maze task modified to explicitly
assess the encoding of spatial memory. The rationale being that if
synaptic plasticity is more easily induced in the presence of apamin,
fewer trials may be required to encode spatial memory in apamin-treated
mice. Naive mice received apamin (0.4 mg/kg, i.p.; n = 10) or 0.9% saline (n = 9) 30 min before daily
training for 6 d (four trials per day) in the water maze task. The
platform location remained fixed throughout all training trials.
Immediately after the fourth, 12th, and 20th training trials, each
mouse received a 30 sec probe test. These interpolated probe tests
assess the development of a spatial bias for the training quadrant of
the pool at an early (probe 1), intermediate (probe 2), and late (probe
3) stage of spatial memory encoding. Apamin treatment accelerated the
development of a spatial bias for the training quadrant during the
first interpolated probe test (probe 1), as shown in Figure
5A. Planned comparisons
analyses revealed that apamin-treated mice spent significantly more
time in the training quadrant than saline-treated mice (mean ± SEM; apamin, 41.1 ± 3.8%; saline, 26.8 ± 2.9%;
t(17) = 2.94; p = 0.009). In addition, apamin-treated mice exhibited more accurate search behavior as indicated by search ratio (Fig. 5B), computed as
the number of crossings into a circular zone encompassing the platform divided by the total number of crossings into all four zones (Fig. 5B, inset diagram) (apamin, 0.43 ± 0.05;
saline, 0.26 ± 0.04; t(17) = 2.52; p = 0.02). Saline-treated mice required 12 training trials to develop this degree of preference (probe 2). Thus,
after minimal training (just four trials), apamin-treated mice
exhibited significant spatial memory of the training quadrant, whereas
control mice exhibited a chance level of performance. There were no
additional differences in performance on probes 2 and 3 between apamin-
and saline-treated mice, indicating that after 12 training trials, the
saline-treated mice had acquired the memory for platform location and
were performing as accurately as apamin-treated mice. Spatial memory
encoded by apamin-treated mice was stable throughout the training
session, because there was no difference in training-quadrant preference across the three interpolated probe tests. Two-factor, repeated-measures (treatment × four trial block) ANOVA on
cumulative distance to platform measures revealed a significant
treatment × four trial block interaction
(F(4,68) = 2.53; p < 0.05) and a significant effect of four trial block
(F(4,68) = 15.75; p < 0.001). Tukey multiple comparisons tests revealed a significant difference between apamin- and saline-treated mice in cumulative distance to platform on the first four trial block (Fig.
5C). The cumulative distance to platform is a score of the
proximity of the mouse to the platform during training and is a more
sensitive measure of spatial behavior than escape latency (Gallagher et al., 1993). The difference in cumulative distance measures between apamin- and saline-treated mice reflects more accurate platform search
behavior by the apamin-treated mice, a finding that is consistent with
the observed differences in spatial search behavior during probe 1. An
identical analysis of escape latency data found a significant effect of
four trial block (F(4,68) = 8.50;
p < 0.001) but no treatment × four trial block
interaction (F(4,68) = 0.44;
p > 0.5) and no significant effect of treatment
(F(4,68) = 0.54; p > 0.5). Apamin treatment did not cause any overt influence on swimming,
and swim speeds were not different between groups (F(1,17) = 0.29; p > 0.5). Analyses restricted to the data from the first four training
trials also indicated no significant differences in escape latencies
(t(17) = 0.33; p > 0.05) or swim speed (t(17) = 0.04;
p > 0.05). Collectively, these results suggest that
apamin-mediated blockade of SK channels facilitated the encoding of
hippocampal-dependent spatial memory.
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Figure 5.
Apamin block of SK channels facilitates
the encoding of spatial memory. A, A modified Morris
water maze task was used to examine the effects of apamin on encoding
of spatial memory. Mice were trained for four trials per day for 6 d, and 30 sec probe tests were presented immediately after the fourth,
12th, and 20th trial. Mean ± SEM percentage of time spent
dwelling (Percent Dwell) in the training quadrant
during the interpolated probe tests revealed that mice treated with 0.4 mg/kg apamin (n = 10) spent significantly more time
in the training quadrant during the first probe test than
saline-treated (n = 9) control mice
(*p < 0.009 vs saline-treated mice on probe test
1; planned comparison Student's t test). The
dashed line at 25% represents chance performance.
AL, Adjacent left; AR, adjacent
right; OPP, opposite; TQ, training
quadrant. B, Mean ± SEM search ratio reflects the
accuracy with which mice search in the correct location within the
training quadrant of the pool. Search ratio is computed as the number
of times the animal crosses into the zone (see circular
regions of inset diagram) encompassing the
platform (shaded zone) divided by the total number of
crossings into all four zones. The dashed line at 0.25 represents chance performance during the probe tests or the lack of
spatial bias for any particular pool location. Apamin-treated mice
exhibited a significantly higher search ratio than saline-treated mice
during the first probe test (*p < 0.02 vs
saline-treated mice on probe test 1; planned comparison Student's
t test). Measures of the percentage of time spent
dwelling in the training quadrant or search ratio from the second or
third probe tests were equivalent between the two groups, indicating
that there were no group differences in platform search behavior after
more training. C, Mean ± SEM cumulative distance
to platform measures of saline- and apamin-treated mice plotted in
blocks of four training trials. This measure indicates the proximity of
the mice to the platform during each training trial. Consistent with
the data from probe test 1, apamin-treated mice swam in closer
proximity to the platform during the first four trial block of training
than saline-treated mice (*p < 0.04; post
hoc Tukey multiple comparisons test).
|
|
Data from the probe test given 24 hr after the final training trial
were examined to test whether memory encoded under SK channel blockade
would be differentially retained. Both groups of mice exhibited a
spatial bias for searching in the training quadrant during the 24 hr
retention probe test. There were no differences between saline- and
apamin-treated mice during the final probe trial with regard to the
percentage of time spent dwelling in the training quadrant (mean ± SEM; saline, 41.6 ± 4.6; apamin, 38.1 ± 4.3;
t(17) = 0.57; p > 0.6) or with regard to the search ratio (saline, 0.43 ± 0.05;
apamin 0.38 ± 0.05; t(17) = 0.64; p > 0.5). Together with the data of Figure
5A-C, it appears that apamin-treated mice encoded the
spatial memory of the platform location with less training than the
saline-treated mice. However, once encoded, there was no difference in
retention of the spatial memory between apamin- and saline-treated mice.
Blocking SK channels accelerates hippocampal-dependent nonspatial
memory encoding.
To further examine the role of SK channels in hippocampal memory,
the effects of apamin on a nonspatial object-recognition task were
examined. This task assesses the encoding and retention of memory for
an object and is sensitive to lesions of the hippocampus (Vnek and
Rothblat, 1996; Clark et al., 2000) and to manipulation of hippocampal
NMDARs (Tang et al., 1999). Given that apamin-treated mice developed a
significant spatial memory for the platform location after minimal
water-maze training, it was hypothesized that apamin would influence
the encoding of object memory in a similar manner. Pilot studies
indicated that during a 5 min sample session, C57BL/6J mice typically
spend an average of 38 sec exploring each sample object. To examine the
influence of apamin on object memory encoding, the amount of sample
object exploration was manipulated. Mice were allowed to explore the
sample objects until they had accumulated object exploration times of
either 19 sec (minimal training) or 38 sec (extensive training). The
results obtained for spatial memory encoding led to our prediction that
apamin would facilitate object memory retention in mice limited to 19 sec of sample object exploration compared with respective
saline-treated mice.
Naive C57BL/6NHsd mice received apamin (0.4 mg/kg, i.p.) or 0.9%
saline 30 min before the sample session. Each mouse was placed into the
arena containing two identical novel objects. Depending on group
assignment, the mouse was removed from the arena after exploring either
sample object for 19 sec (minimal training) or 38 sec (extensive
training). During the sample session, there was no significant
difference between saline- and apamin-treated mice with regard to the
time required to reach the respective 19 or 38 sec sample object
exploration limit (t(17) = 1.31 and 0.04, respectively; p values of >0.05) (Fig.
6A), indicating that all mice exhibited the same curiosity and motivation. Object memory retention was assessed during a test session 24 hr later, in which each
mouse was allowed to explore the arena containing one of the familiar
objects from the sample session and a novel object. Saline-treated mice
limited to 19 sec of sample object exploration exhibited a weaker
preference for the novel object during the test session compared with
mice permitted 38 sec of sample object exploration (Fig.
6B). Planned comparisons analysis revealed that apamin-treated mice limited to 19 sec of sample object exploration exhibited a stronger preference for the novel object compared with the
respective saline-treated mice (t(17) = 2.17; p = 0.04) (Fig. 6B). These
data suggest that apamin is capable of facilitating object memory
encoding. There was no difference in novel object preference ratio
between saline- and apamin-treated mice permitted 38 sec of sample
object exploration (t(17) = 0.11;
p > 0.05), indicating that both groups exhibited
equivalent object memory retention. In accordance with our findings of
apamin-treated mice in the Morris water-maze task, these findings
suggest that apamin block of SK channels facilitates the encoding of
nonspatial memory, perhaps by reducing the threshold for memory
formation.
View larger version (16K):
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|
Figure 6.
Apamin block of SK channel activity
facilitates the encoding of nonspatial object memory but does not
influence the retention of object memory. Object-recognition
memory was quantified by computing the novel object preference ratio,
the amount of time spent exploring the novel object during the test
session divided by the total time spent exploring both the familiar and
novel object. A, The object recognition task was
modified to test the influence of apamin on object memory encoding. As
described in Materials and Methods, during the sample session, saline-
and apamin-treated mice were restricted to either 19 sec (minimal
training) or 38 sec (extensive training) of sample object
exploration. The amount of time required to accumulate either 19 or 38 sec of sample object exploration did not differ between apamin- and
saline-treated mice (p values >0.05; unpaired
Student's t test). B, Restricting the
amount of object exploration during the sample session to 19 sec
weakens the degree of preference exhibited by the mouse during a test
session 24 hr later. This is illustrated by the lower novel object
preference ratio of the saline-treated mice (n = 9)
limited to 19 sec of sample object exploration. However, apamin (0.4 mg/kg)-treated mice (n = 10) that were limited to
only 19 sec of sample object exploration exhibited a significantly
greater novel object preference during the 24 hr test session
(*p < 0.04 vs saline-treated mice permitted 19 sec of object exploration; planned comparison Student's
t test). When apamin (0.4 mg/kg)-treated
(n = 10) and saline-treated (n = 9) mice were permitted 38 sec of sample object exploration, there was
no difference in novel object preference ratio during the 24 hr test
session. Each dashed line at 0.5 represents chance
performance or a lack of discrimination between the novel and familiar
object. C, Object memory retention decays over a similar
time course in apamin- and saline-treated mice. Both apamin- and
saline-treated mice exhibited similar strong preference for the novel
object during a 24 hr retention test; mean ± SEM novel object
preference ratios were not significantly different. Four days later,
the same mice received a second sample session with two new objects.
When tested for retention 48 hr later, both apamin- and saline-treated
mice failed to show a strong preference for the novel object over the
familiar object. These data indicate that apamin does not affect the
retention of object memory.
|
|
The retention of object memory decays faster in hippocampal-lesioned
rodents (Vnek and Rothblat, 1996; Clark et al., 2000) and is sensitive
to genetic manipulation of the hippocampal NMDAR (Tang et al., 1999).
Hippocampal-lesioned rats fail to retain object memory over a 24 hr
delay (Clark et al., 2000) but are able to retain object memory over a
5 min delay (Mumby et al., 2002). The influence of systemic apamin on
the rate of decay of object memory retention was examined in a second
cohort of C57BL/6NHsd mice. During a sample session, apamin- (0.4 mg/kg, i.p.) and saline-treated mice were exposed to two identical
sample objects for 5 min. Both groups exhibited a similar preference
for the novel object during the 24 hr test session, as shown in Figure
6C, indicating that apamin did not influence memory
retention at 24 hr, consistent with the 38 sec data of Figure
6B. Four days later, the same groups were exposed to
a second set of sample objects and then tested for retention 48 hr
later. As depicted in Figure 6C, neither group exhibited a
significant preference for the novel object at the 48 hr test session,
suggesting that object memory decayed over the same rate between the
two groups. These data indicate that apamin did not influence object
memory retention.
| |
DISCUSSION |
The present study demonstrates that blockade of synaptically
activated SK channels increases excitability and decreases the threshold for the induction of hippocampal synaptic plasticity via a
postsynaptic mechanism that requires the activation of NMDARs. The
reduced threshold for induction of synaptic plasticity is associated
with facilitated memory encoding. This enhancement is correlated with
changes in the induction of synaptic plasticity but is not necessarily
attributable to these changes, because there is no way to rule out the
effects of apamin on other brain structures that can influence
hippocampal function.
Neural circuits derive flexibility from activity-driven bidirectional
modification of synaptic strength (Sejnowski, 1977; Bienenstock et al.,
1982). An important characteristic of this process is the threshold for
synaptic modification (Bear, 1995), which is defined by the
frequency-response function for the induction of synaptic plasticity.
As postsynaptic activity increases, the threshold for LTD is reached
first, and an additional increase leads to a transition from LTD to
LTP. This transition represents the synaptic modification threshold
(Bear, 1995). A prominent model for the regulation of the synaptic
modification threshold proposes that the direction of altered synaptic
efficacy, potentiation, or depression is determined by the level of
postsynaptic Ca2+ during neural activity
(Lisman, 1989; Artola and Singer, 1993; Malenka and Nicoll, 1993). The
rise in Ca2+ within the dendritic spine is
the critical trigger for synaptic plasticity. Stronger depolarization
allows more Ca2+ to enter and leads to
synaptic potentiation (Lisman, 1989; Artola and Singer, 1993; Bliss and
Collingridge, 1993; Cummings et al., 1996; Malenka and Nicoll, 1999),
whereas weaker depolarization leads to less
Ca2+ influx and synaptic depression
(Mulkey and Malenka, 1992; Dudek and Bear, 1993). Therefore, any
manipulation that influences the magnitude or dynamics of
Ca2+ increase within dendritic spines may
profoundly influence the form of the resulting synaptic plasticity.
Synaptic activation of the channels underlying the
IsAHP (Lancaster et al., 2001; Martin
et al., 2001) regulates synaptic efficacy and may influence the
threshold for synaptic plasticity, as hypothesized by previous studies
(Sah and Bekkers, 1996). Our results showed that application of apamin
caused a shift of the synaptic modification threshold to lower
frequencies, an effect that is consistent with facilitated induction of
synaptic plasticity. Apamin-sensitive SK channels underlie the mAHP in
CA1 neurons, which peaks ~200 msec after the action potential (Sah
and Clements, 1999; Stocker et al., 1999), a time course that may
enable the mAHP to influence neuronal discharge activity, and the
integration of synaptic events as the rate of afferent stimulation
increases toward the threshold for synaptic plasticity (5-20 Hz).
These are precisely the stimulation frequencies around which apamin exerted its significant effects on the induction of synaptic plasticity.
Our results suggest that SK channel activity modulates the induction of
synaptic plasticity that requires postsynaptic depolarization and NMDAR
activation. Postsynaptic depolarization induced by repetitive synaptic
stimulation raises intracellular Ca2+
levels through voltage-gated Ca2+ channels
or NMDARs, permitting the activation of SK channels. By hyperpolarizing
the postsynaptic membrane, SK channels decrease excitability and
modulate the activation of NMDARs, which involves voltage-dependent
removal of the Mg2+ block (Mayer et al.,
1987). By affecting the degree of NMDAR activation and the subsequent
Ca2+ entry, SK channels may modulate the
induction of synaptic plasticity. Our experiments suggest that SK
channels are dendritically localized. Although direct evidence for the
distribution of SK channels in the dendrites is currently unavailable,
it has been suggested that apamin-sensitive SK channels are located
predominantly in proximal and distal dendrites of motor neurons
(Cangiano et al., 2002). In addition,
Ca2+-activated
K+ channels have been reported in the
dendrites of mammalian neurons (Andreasen and Lambert, 1995; Sah and
Bekkers, 1996; Schwindt and Crill, 1997).
Synaptic plasticity is believed to represent, at least in part, the
cellular mechanisms responsible for learning and memory. It is
generally accepted that some form of an increase in synaptic efficacy
in the hippocampus is necessary for encoding spatial memory in the
water maze task (Moser et al., 1998). Whether such memory formation in
the hippocampus is dependent on LTP or LTD has been difficult to
establish (Holscher, 1997; Jeffery, 1997; Shors and Matzel, 1997). In
the present study, blockade of SK channels increases excitability,
reduces the threshold for hippocampal synaptic plasticity, and
facilitates hippocampal memory encoding. Systemically administered
apamin crosses the blood-brain barrier (Habermann, 1984), and high
densities of apamin-sensitive SK channels are present in limbic
regions, including the hippocampus (Mourre et al., 1987; Gehlert and
Gackenheimer, 1993; Stocker and Pedarzani, 2000). Apamin-treated mice
acquired a spatial memory for the water maze platform location after
just four training trials (minimal training), whereas saline-treated
mice required as many as 12 trials to demonstrate spatial memory
acquisition. In the object recognition task, apamin-treated mice
exhibited a significantly stronger test session preference for the
novel object than saline-treated mice when limited to 19 sec of sample
object exploration (minimal training). The parallel between the
reduction of the threshold for synaptic plasticity and the improved
memory encoding after minimal spatial or nonspatial training suggests a
correlation between the facilitation of the induction of synaptic
plasticity and memory encoding. The amount of induced plasticity cannot
be equated with the rate of learning, because control and
apamin-treated slices showed the same amount of LTP and LTD. However,
the rate of learning seems to be dependent on the threshold for the
induction of synaptic plasticity.
Previous studies indicate that apamin enhances spatial memory in mice
with lesions of the hippocampal formation but have failed to detect an
influence of apamin on memory retention in intact mice after extensive
training (Ikonen et al., 1998; Ikonen and Riekkinen, 1999). Moreover,
it was proposed recently that there are differences in apamin
sensitivity between mice and rats, with rats being relatively
insensitive to the cognitive effects of apamin (van der Staay et al.,
1999). However, this claim is not substantiated by recent findings.
Independent laboratories have demonstrated that in rats, apamin
enhances the induction of synaptic plasticity (Behnisch and Reymann,
1998; Norris et al., 1998) and facilitates nonspatial memory (Deschaux
et al., 1997; Fournier et al., 2001). Our data suggest that apamin
exerts its influence on an early stage of memory encoding, an effect
that may not have been detected given the approaches used previously.
This indicates that apamin facilitated memory after minimal spatial or
nonspatial training. Apamin did not have a significant effect on memory
retention in mice after extensive spatial training, consistent with
previous reports of the effects of apamin in mice and rats (Ikonen et
al., 1998; Ikonen and Riekkinen, 1999; van der Staay et al., 1999).
From our behavioral data, no distinction can be made between an effect
of apamin that leads to enhanced memory formation and that of an
enhanced processing of the sensory input that precedes the formation of
memory. However, the results suggest that it is unlikely that the
enhancing effects of apamin are a consequence of sensory, motor, or
attentional influences. If apamin was to influence sensory or
attentional mechanisms, then apamin treatment would have enhanced
object memory retention in both groups of mice, those limited to 19 sec
of sample exploration as well as those allowed 38 sec of sample
exploration. The beneficial effect of apamin on spatial memory encoding
in the Morris water maze cannot be attributed to enhanced motor
function, because no differences in swim speed between apamin- and
saline-treated mice were observed.
Collectively, the data from electrophysiological and behavioral studies
indicate that blockade of SK channels by apamin increases excitability,
shifts the threshold for the induction of synaptic plasticity, and
facilitates hippocampal-dependent memory. The behavioral significance
of this apamin-induced increase in excitability is to facilitate the
processing of to-be-remembered information. The behavioral studies do
not indicate whether the apamin-mediated enhancement in memory is
caused by a facilitation of the induction of LTP or LTD. However, the
shift in the threshold for synaptic plasticity produced by apamin could
represent a mechanism for ensuring that there is coincident stimulation
of hippocampal NMDARs leading to an enhancement of synaptic efficacy
during the initial stages of learning. Learning-induced reduction of
the AHP has been shown to underlie learning and memory in other
behavioral paradigms. A potentiation of EPSPs and a reduction in the
mAHP and sAHP currents is associated with classical conditioning of the
eye-blink response in rabbits (Disterhoft et al., 1988; LoTurco et al.,
1988; Coulter et al., 1989) and with olfactory operant conditioning in
rats (Saar et al., 1998). Single-unit recording studies of hippocampal
neurons from behaving rabbits during eye-blink conditioning trials have
revealed increases in neuronal firing rates that are specific to
learning (Berger et al., 1983; McEchron and Disterhoft, 1999).
Therefore, the AHP is a negative regulator of learning, and reduction
of the AHP by apamin appears to facilitate learning and memory.
Together with the results presented here, it appears that
apamin-sensitive SK channels represent a neural mechanism capable of
regulating hippocampal-dependent memory.
| |
FOOTNOTES |
Received May 10, 2002; revised Sept. 24, 2002; accepted Sept. 24, 2002.
This work was supported by a grant from the Medical Research Foundation
of Oregon (T.T.) and by grants from the National Institutes of Health
(J.M., J.P.A.). We thank Drs. Craig Jahr, Laurence Trussell, and
members of their laboratories for helpful discussions. We also thank
Sophie Davis (Oregon Health and Science University/Portland State University Saturday Academy 2001 summer high school science apprenticeship program) for help with behavioral testing and Laura Tull, Dr. Anastassios Tzingounis, and Dr. Jacques Wadiche for helpful
comments on this manuscript.
Correspondence should be addressed to Dr. Thanos
Tzounopoulos, Auditory Neuroscience, L-335A, Oregon Hearing Research
Center, Oregon Health and Science University, 3181 Southwest Sam
Jackson Park Road, Portland, OR 97239-3098. E-mail: tzounopo{at}ohsu.edu.
| |
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ABSTRACT
INTRODUCTION
