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The Journal of Neuroscience, August 15, 1998, 18(16):6071-6080
When Are Class I Metabotropic Glutamate Receptors Necessary for
Long-Term Potentiation?
Volker W.
Wilsch1,
Thomas
Behnisch1,
Tino
Jäger1,
Klaus G.
Reymann1, 2, and
Detlef
Balschun1
1 Leibniz Institute for Neurobiology, Department of
Neurophysiology, and 2 Research Institute of Applied
Neurosciences gGmbH, D-39008 Magdeburg, Germany
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ABSTRACT |
The involvement of metabotropic glutamate receptors (mGluRs)
in hippocampal long-term potentiation (LTP) is a matter of
controversial debate. Using [Ca2+]i
measurements by confocal laser scanning microscopy and field recordings
of EPSPs (fEPSPs) in the hippocampal CA1-region, we found that
the efficacy of the broad-spectrum mGluR-antagonist (S)- -methyl-4-carboxyphenylglycine (MCPG) and of
(S)-4-carboxy-phenylglycine (4-CPG), a selective
antagonist at class I mGluRs, in LTP is contingent on the tetanization
strength and the resulting [Ca2+]i
response. As indicated by experiments in which we blocked
voltage-dependent calcium channels (VDCCs) and intracellular
Ca2+ stores (ICSs), the functional significance of
class I mGluRs in LTP is confined to certain types of potentiation,
which are induced by weak tetanization protocols and require the
release of Ca2+ from ICSs for induction. During
strong tetanic stimulation, this Ca2+ source is
functionally bypassed by activating VDCCs.
Key words:
class I metabotropic glutamate receptors; long-term
potentiation; intracellular calcium concentration; intracellular
calcium stores; voltage-dependent calcium channels; hippocampus
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INTRODUCTION |
The induction of long-term
potentiation (LTP), an activity-dependent form of synaptic plasticity,
was proven to require the influx of Ca2+ through the
NMDA type of glutamate receptors (NMDARs), under most
experimental conditions (Bliss and Collingridge, 1993 ; Malenka, 1994).
However, because an activation of NMDARs alone results in decremental
short-term potentiation (Collingridge et al., 1983; Kauer et al.,
1988), other mechanisms such as a coactivation of metabotropic
glutamate receptors (mGluRs) have been suggested to be involved.
Until now, eight subtypes of mGluRs have been described and assigned to
three different classes according to their sequence homology,
pharmacological characterization, and coupling to second messenger
pathways. While the activation of class I mGluRs (mGluR1, 5) stimulates
phosphatidylinositol 4,5-bisphosphate hydrolysis [producing inositol
1,4,5-trisphosphate (IP3) and diacylglycerol], mGluRs of class II (mGluR2, 3) and class III (mGluR4, 6, 7, 8) are
negatively coupled to adenylyl cyclase (Nakanishi, 1994; Conn and Pin,
1997).
The involvement of mGluRs in hippocampal synaptic plasticity has
been a matter of controversial debate during the last few years. In
particular, experiments using the class I/II specific antagonist
(S)--methyl-4-carboxyphenylglycine (MCPG) yielded conflicting results. While some authors reported an inhibition of LTP
(Bashir et al., 1993; Bortolotto et al., 1994; Brown et al., 1994;
Richter-Levin et al., 1994; Little et al., 1995; Riedel et al., 1995),
in other studies the MCPG actions could not be confirmed (Chinestra et
al., 1993; Manzoni et al., 1994; Selig et al., 1995; Thomas and
O'Dell, 1995). The issue of whether MCPG-sensitive mGluRs are involved
in NMDAR-dependent synaptic plasticity was further confounded by the
contrasting results of studies using mGluR1 and mGluR5 knock-out mice
(Aiba et al., 1994; Conquet et al., 1994; Lu et al., 1997).
An intriguing possibility for resolving the controversy was provided by
the "molecular switch hypothesis" (Bortolotto et al., 1994).
According to this hypothesis, activation of mGluRs before LTP sets an
input-specific molecular switch that then negates the necessity of
further mGluR activation during LTP induction. However, other groups
failed to confirm the existence of such a molecular switch (Selig et
al., 1995; Thomas and O'Dell, 1995), giving a clear indication that
the switch is not a general mechanism of synaptic plasticity but rather
confined to certain experimental conditions.
Therefore, we pursued another idea to approach this question and
focused on the effects of class I mGluRs on the
IP3-mediated Ca2+ release from
intracellular Ca2+ stores (ICSs) (Murphy and Miller,
1988; Berridge, 1993; Jaffe and Brown, 1994; Shirasaki et al., 1994;
Phenna et al., 1995). Several laboratories have shown that the rise in
intracellular Ca2+ concentration
([Ca2+]i) is a critical factor
for LTP induction (Lynch et al., 1983; Malenka et al., 1988, 1992) and
that the contribution of Ca2+ from ICSs may
represent a critical factor for generating a long-lasting potentiation
(Harvey and Collingridge, 1992; Behnisch and Reymann, 1995).
We suggest that this Ca2+ source should be
particularly important under conditions where Ca2+
entry through NMDARs and voltage-dependent calcium channels (VDCCs) does not attain the threshold concentration for triggering subsequent transduction pathways that are critical for LTP maintenance.
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MATERIALS AND METHODS |
Hippocampal slice preparation
Hippocampal slices were prepared from male rats (7-8 weeks old)
of the Wistar outbred strain MOL: WIST (SHOE). After
decapitation and dissection of the hippocampus, 400-µm-thick slices
were cut in cold oxygenated physiological solution [artificial CSF
(ACSF) (in mM): NaCl 124, KCl 4.9, MgSO4 1.3, CaCl2 2.5, KH2PO4 1.2, NaHCO3 25.6, D-glucose 10, saturated with 95%
O2, 5% CO2, pH 7.4] using a
tissue chopper. The slices were submerged and permanently perfused with
32°C ACSF.
Electrophysiological long-term recordings
Synaptic responses were elicited by stimulation of the Schaffer
collateral-commissural fibers in stratum radiatum of the CA1 region
using lacquer-coated stainless steel stimulating electrodes. Glass
electrodes (filled with ACSF, 1-4 M ) were placed in the apical
dendritic layer to record field EPSPs (fEPSPs). The initial slope of
the fEPSP was used as a measure of this potential. The test stimulation
strength was adjusted to 35% of the maximum. During baseline
recording, four single stimuli (10 sec interval) were averaged every 5 min. After tetanization, recordings were taken every 10 min over a
period of at least 120 min. Once a stable baseline had been
established, LTP was induced by one of the following tetanization
paradigms.
Strong tetanization. Three trains of 500 msec duration at
100 Hz and 0.2 msec pulse width, separated by 2 min intervals, induced a stable potentiation of fEPSP of at least 180 min in control experiments.
Weak tetanization. (1) Four paired pulses (10 msec interval,
0.2 msec pulse width) were applied at the theta frequency of 5 Hz. The
tetanization was strengthened either by adding two more paired pulses
up to eight × two pulses or further by increasing the number of
pulses (eight × four). (2) A single train of 400 msec duration at
100 Hz and 0.2 msec pulse width was applied. These weak
tetanization protocols triggered a potentiation that returned to
baseline level within 180 min.
In some experiments, two independent pathways were stimulated in the
same slice by placing the stimulation electrodes symmetrically to the
recording electrode into the apical dendritic layer at a different
distance from the pyramidal layer.
The mGluR antagonists MCPG and
(S)-4-carboxyphenylglycine (4-CPG) (Tocris, Bristol,
UK) were dissolved in ACSF and bath-applied from 10 min before until 5 min after tetanization. Thapsigargin (Calbiochem, Bad Soden, Germany),
a potent and selective inhibitor of intracellular
Ca2+ pumps, and the L-type VDCC blocker nimodipine
(Sigma, Deisenhofen, Germany) were initially dissolved in
dimethylsulfoxide (DMSO) and further diluted with ACSF (final
concentration of DMSO <0.01%). Thapsigargin was added to the bath
from 30 min before until 5 min after tetanus; nimodipine was added
according to the same time schedule as MCPG and 4-CPG. The drugs were
applied either alone or in combination, as indicated in the text. All
solutions were adjusted to pH 7.4. For statistical analysis, the
Mann-Whitney U test (independent samples) and the Wilcoxon
matched pairs signed rank test were used with a significance level of
p < 0.05.
Confocal microscopy
Experiments were performed on ventral transverse hippocampal
slices (250 µM thick) from 20-d-old male Wistar rats in
the same solutions and conditions as the extracellular experiments.
Pyramidal CA1 neurons and their Ca2+ transients were
visualized with a Odyssey XL confocal laser scanning microscope (Noran Instruments, Middleton, WI) mounted on an Axioskop-FS upright microscope (Zeiss, Jena, Germany). Image acquisition was performed using Intervision software (Noran Instruments) on a Silicon Graphics Indy workstation. All recordings were performed with a 488 nm excitation filter and a 515 nm long-pass emission filter. The slit
aperture on the photomultipliers set was adjusted to 100 µm width. A
40× water-immersion objective (NA = 0.75) was used to visualize
neurons.
CA1 pyramidal cells were impaled with potassium acetate (2 M)-filled borosilicate glass microelectrodes (80-150 M)
(Clark, Pangbourne, UK). The tips of these sharp electrodes were filled with the Ca2+-sensitive dye Calcium Green-1 (2 mM; Molecular Probes, Leiden, Netherlands). For the
experiments involving bath application of 4-CPG, and coapplication of
4-CPG and nimodipine, 30 mM QX-314 (Alomone Labs,
Jerusalem, Israel) was added to the dye solution. A monopolar
stimulating electrode was positioned in CA1 stratum radiatum. Only
neurons with a membrane potential below  55 mV [recorded with an npi
SEC 1L-amplifier (NPI Electronic, Tamm, Germany) at bridge-mode] were
used. The electrophysiological properties of the neurons were
controlled during the whole experiment. The dye was injected into the
neurons by applying a steady-state hyperpolarizing current of 100-400
pA for 15-20 min. Well stained, in focus dendrite regions 80-200 µm
from soma were chosen for recording the Ca2+
responses to different tetani. Tetanizations were performed in a time
interval of 2 min with biphasic pulses. The changes in fluorescence
intensity were averaged over 66.7 msec (average of eight images). For
data analysis, four regions of interest (ROI) were selected on the
dendritic tree. The fluorescence intensities of these four ROI were
averaged, and a background correction was performed, i.e., a nearby
nonactive region of the same size as the recording region was measured
in parallel and subtracted. The results were given as
F/F0 whereby
F0 was the averaged intensity before the
tetanization.
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RESULTS |
Because most of the studies that addressed the functional role of
mGluRs in LTP were performed in the CA1 region of the hippocampus, we
recorded fEPSPs in the apical dendritic layer of this area by
stimulating the Schaffer collateral-commissural fibers. The initial
slope of the fEPSPs was used as a measure of synaptic responses. In the
first series of experiments we tested whether the ability of mGluR
antagonists to block LTP depends on tetanization strength. In the
strong tetanization paradigm (3 × 100 Hz, 500 msec, 2 min
interval between trains), which led to a stable potentiation lasting
>240 min under control conditions, the application of MCPG (400 µM) affected neither the initial magnitude (MCPG group: 213 ± 12%, n = 7; control: 220 ± 7%,
n = 7) nor the time course of potentiation (after 240 min: 133 ± 6% and 137 ± 5%, respectively) (Fig.
1A). Because MCPG is a
broad-spectrum antagonist acting on class I mGluRs, and with a somewhat
lower affinity at mGluRs of class II (Davies et al., 1995; Sekiyama et
al., 1996), we repeated the same experiments with 4-CPG, which
represents in the employed concentration range a specific antagonist
toward class I mGluRs. 4-CPG (100 µM) had no effect on
the initial potentiation (4-CPG group: 208 ± 9%,
n = 7; control: 206 ± 10%, n = 7) and the maintenance of LTP (240 min after tetanus: 135 ± 8%
and 132 ± 6%, respectively) (Fig. 1B). From
these experiments, we concluded that activation of mGluR class I is not
mandatory for the induction of a long-lasting potentiation by strong
tetanization.
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Figure 1.
MCPG (400 µM; n = 7) (A) and 4-CPG (100 µM;
n = 7) (B) did not influence
LTP induced by a strong tetanization (3 × 100 Hz, 500 msec, 2 min
interval between trains). The potentiation persisted for at least 240 min. The tetanus was applied at the time point 0. Horizontal
bars under the time scale indicate the time of drug
application. Analog traces represent typical recordings of single
experiments taken 10 min before tetanization (1)
and 120 min after tetanization (2).  ,
Drug-treated groups;  , controls. Calibration: 2 mV, 3 msec.
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To test whether these drugs can affect a potentiation induced by a weak
tetanic stimulation, we conducted experiments in which we used
tetanization paradigms consisting of either four paired pulses (10 msec
interval, applied at the theta frequency of 5 Hz) or a single 100 Hz
train of 400 msec duration.
"Paired-pulse tetanization" induced an LTP that lasted ~180 min
under control conditions. Application of 400 µM MCPG did
not influence the initial magnitude of potentiation (MCPG group:
179 ± 6%; control: 190 ± 7%) but significantly impaired
the maintenance of LTP beginning 50 min after the tetanus
(n = 7; p < 0.05) (Fig. 2A). After 120 min, the
fEPSP potentiation of the MCPG-treated slices had returned to
baseline values, whereas the control group was still above baseline
(110 ± 2%; n = 9). Similarly, application of 50 µM 4-CPG (n = 6) led to a faster decline
of LTP compared with control (from 65 min after tetanus) but left the
initial potentiation untouched (181 ± 9% 4-CPG experiments;
192 ± 7% control) (Fig. 2B). The effect of
4-CPG on LTP induced by the weak 100 Hz tetanization resembled the
effect observed in the previous tetanization paradigm, i.e., beginning
90 min post-tetanus, the potentiation of the 4-CPG group was
significantly impaired (102 ± 6%; n = 6) as
compared with control (122 ± 5%; n = 8) (Fig. 2C).
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Figure 2.
LTP induced by a weak tetanization protocol was
susceptible to the action of MCPG (A) or 4-CPG
(B-D). The tetanization consisted of either
four × two pulses (200 msec interval between pulse pairs)
(A, B) or a single 100 Hz train, 400 msec duration
(C). In the experiments depicted in
D, two independent pathways in the same slice were used
to allow a direct comparison of the effects of 4-CPG on LTP generated
by induction protocols of different strength. The groups treated with
mGluR antagonists are indicated by open symbols, and
their respective controls are indicated by closed
symbols. A, Application of 400 µM
MCPG led to a significant reduction of LTP, starting at 50 min
post-tetanus (n = 7, as compared with controls,
n = 9; p < 0.05).
B, 4-CPG (50 µM) caused a significant
blockade of LTP from 65 min after tetanus (4-CPG groups:
n = 6; controls: n = 8;
p < 0.05). C, Similarly, an LTP
induced by the weak 100 Hz tetanization decayed faster after
application of 4-CPG (50 µM). D, 4-CPG (50 µM) significantly impaired a decremental LTP that was
induced by a weak tetanization (single 100 Hz train, 400 msec duration;
circles) of the first pathway, but had no significant
effect on a robust potentiation (3 × 100 Hz, 500 msec duration, 2 min interval between trains; squares) generated 10 min
afterward by strong tetanization of the second pathway. Note that in
D the first sampling time after tetanus was 5 min, but
it was 1 min in A-C. Analog traces represent typical
recordings of single experiments taken 10 min before tetanization
(1) and 60 min after tetanization
(2). Calibration 2 mV, 3 msec.
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To verify the actions of 4-CPG with a different experimental approach,
we used two independent stimulation pathways in the same slice
(n = 6). A weak tetanization was applied to the first pathway (single 100 Hz train, 400 msec duration) followed 10 min afterward by a strong tetanization (3 × 500 msec, 100 Hz, 2 min interval between trains) of the second pathway. 4-CPG (50 µM) significantly impaired the decremental LTP that was
induced by the weak tetanization (4-CPG group: 109 ± 4%;
control: 124 ± 6%, at 100 min; p < 0.05) but
had no significant effect on the robust potentiation generated by the
strong tetanization paradigm (4-CPG group: 161 ± 15%; control:
174 ± 14%, at 100 min) (Fig. 2D).
Because MCPG and 4-CPG were effective only in the weak tetanization
paradigm, we investigated whether the efficiency of class I antagonists
is dependent on the tetanization strength. To test this, the
tetanization strength of the weak tetanization paradigm of four bursts
of two pulses at 5 Hz was gradually increased by adding more bursts or
by increasing the number of pulses per burst. The resulting fEPSP slope
potentiation (normalized to controls 90 min after tetanization) was
compared with the fEPSP slope potentiation that was obtained with the
other tetanization protocols used in this study. The results depicted
in Figure 3 (columns 1-5,
left) clearly indicate that the 4-CPG effect is contingent on
tetanization strength. The fEPSP slope potentiation was mostly impaired
using tetanization protocols of four × two pulses (82.4 ± 2.5%, n = 7; p < 0.05; left
column) and 100 Hz, 400 msec duration (83.4 ± 5.7%,
n = 5; p < 0.05). The effect decreased
if six instead of four paired pulses were applied in the paired-pulse
protocol (89.5 ± 2.9%, n = 5; p < 0.05). Enhancing the tetanus strength either by adding two more
paired pulses (eight × two) (data not shown) and further by
increasing the number of pulses (eight × four) or by
applying a strong tetanization of 3 × 500 msec at 100 Hz (2 min
interval between trains) abolished the effect of 4-CPG on LTP
(eight × four pulses: 103.9 ± 10.6%, n = 5; 3 × 500 msec: 100.4 ± 2.3%, n = 6).
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Figure 3.
The effectiveness of 4-CPG on LTP was contingent
on the strength of tetanization. The fEPSP slope potentiation
(normalized to controls 90 min after tetanization) was mostly impaired
using tetanization protocols of four × two pulses (82.4 ± 2.5%, n = 7; p < 0.05;
left column) and 100 Hz, 400 msec duration (83.4 ± 5.7%, n = 5, p < 0.05). The
effect decreased if six instead of four paired pulses were applied in
the paired-pulse protocol (89.5 ± 2.9%, n = 5; p < 0.05). Enhancement of the tetanus strength,
by adding two more pulses (8 × 2) (data not shown) or by
increasing the number of pulses (8 × 4) or by applying a strong
tetanization of 3 × 100 Hz (500 msec, 2 min interval between
trains) abolished the effect of 4-CPG on LTP (103.9 ± 10.6%,
n = 5, and 100.4 ± 2.3%,
n = 6, respectively). Coapplication of 4-CPG (100 µM) and nimodipine (10 µM) resulted in a
clear decrease of potentiation to 67.8 ± 6.9%
(n = 7). This effect could be mimicked by
coapplication of thapsigargin (TG) and nimodipine
(n = 7).
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The experiments presented above showed that the effectiveness of MCPG
and 4-CPG on LTP is confined to weak tetanization paradigms. Because it
has been demonstrated that the magnitude of Ca2+
influx through NMDARs may be a critical factor in determining whether a
robust or decremental potentiation is induced (Malenka et al., 1992),
we suggested that the involvement of class I mGluRs in LTP may depend
on the level and dynamics of [Ca2+]i
during tetanization. To examine how an increment of the duration of
tetanization affects the rise of
[Ca2+]i in dendrites, pyramidal CA1
neurons were loaded with the Ca2+-sensitive dye
Calcium Green-1 and stimulated by a monopolar stimulating electrode
positioned 80 µm from soma in CA1 stratum radiatum. Tetanizations of
different durations (and pulse widths) were applied in a time interval
of 2 min, and the Ca2+ responses of selected
dendritic regions were visualized by confocal laser scanning microscopy
and subsequently analyzed. As exemplified in Figure
4A, weak 100 Hz
tetanization protocols (e.g., 200 msec, pulse width 0.1 msec) induced a
submaximal, short-lasting rise of
[Ca2+]i. Augmenting the pulse width or
increasing the duration of tetanization advanced the
[Ca2+]i response toward maximum
values. After approaching these peak Ca2+
concentrations, any further extension of tetanization broadened the
peak and slowed down the decay. For example, a 1 sec train of 100 Hz
caused an elevation of [Ca2+]i that
lasted for more than 2 sec. Application of a weak tetanization paradigm
of four × two pulses at 100 Hz (200 msec interburst interval) triggered a [Ca2+]i rise that
resembled the [Ca2+]i responses
obtained with the common 100 Hz protocols but was superimposed by steep
pinnacles that were synchronized with the interburst interval of 200 msec (5 Hz) (Fig. 4A, shaded area). It is
important to note that the Ca2+ transients to
different tetanization protocols were found to be independent of the
sequence of application. As depicted in Figure 4D,
the averaged areas of the fluorescence intensity changes (AreaF/F0) were correlated linearly,
to both the duration of tetanic 100 Hz stimulation and the pulse width that we used [correlation coefficients of 0.99; data of pulse width
0.2 msec (data not shown)]. The AreaF/F0 of
the tetanus of four × two pulses was comparable to the 400 msec
tetanus (100 Hz). This finding corresponds very well with the duration
of potentiation obtained with these stimulation protocols in the
extracellular experiments (Fig. 2A-D) (additional
data not shown).
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Figure 4.
Ca2+ imaging of the rise of
[Ca2+]i in the dendritic tree of CA1
neurons (filled with the Ca2+-sensitive dye Calcium
Green-1) on stimulation with different tetanization protocols and bath
application of the mGluR class I antagonist 4-CPG (50 µM)
and the L-type VDCC antagonist nimodipine (10 µM).
A, Averaged Ca2+ response curves
(transients) of seven neurons to a single set of tetanization
paradigms. The Ca2+ transients of four dendritic
regions were averaged. The tetanization protocols corresponding to the
curves are indicated by an arrow. An increasing duration
of the 100 Hz stimulation led initially to an increment of the peak
amplitude, but after reaching a maximum amplitude the high
Ca2+ level is maintained, followed by a slower decay
(1 sec train). Application of the standard weak tetanization paradigm
of four bursts of two pulses at 100 Hz (200 msec interburst interval)
triggered a [Ca2+]i rise that
resembled the [Ca2+]i responses
obtained with the common 100 Hz protocols but was superimposed by steep
pinnacles that were synchronized with the interburst interval of 200 msec (5 Hz) (shaded area). B, C,
Representative images of the Ca2+ response of one
neuron. The Ca2+ response to a weak
(200 msec) (B) and a strong tetanization (1 sec)
(C) is illustrated. The examples were taken at
the onset of tetanization (top images), at the maximum
of [Ca2+]i elevation
(middle), and during the decay phase of the response
(bottom). Note the clear difference in the
Ca2+ level during the decay of response at 933 msec
(bottom traces). D, As indicated by the
averaged areas of the fluorescence intensity changes (Area
F/F0), the rise of
[Ca2+]i was closely correlated to both
the duration of tetanic 100 Hz stimulation and the pulse width that was
used (correlation coefficients of 0.99; data not shown of pulse width
0.2 msec). The area below the
F/F0 curves was calculated as
AreaF/F0 =  B
(F/F0 1) dt;
B = [0 sec, 8 sec]. E, F, After
a tetanization of four × two pulses, bath application of 4-CPG
(50 µM) led to a significant reduction
(p < 0.05) of
AreaF/F0 to 67%
(F), which was caused predominantly by a slower
rise and earlier decay of [Ca2+]i.
Note that the effect of 4-CPG was reversible (wash out
line in E). G, Only the coapplication of
4-CPG and nimodipine caused a significant reduction of
AreaF/F0 (78%;
p < 0.05) during strong tetanization (1 sec, 100 Hz). The application of 4-CPG alone had no effect.
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Although these data provide only a momentary and localized image of the
[Ca2+]i dynamics occurring in the
dendritic regions, they support the hypothesis that the intradendritic
level of Ca2+ is closely correlated to the type and
duration of tetanization. Next, we examined by confocal laser scanning
microscopy whether the elevation of
[Ca2+]i after weak tetanic stimulation
can be impaired by an inhibition of class I mGluRs, as implied by the
coupling of class I mGluRs to IP3-sensitive ICSs and
suggested by the action of 4-CPG in the weak potentiation paradigms
(Fig. 2B-D). As shown in Figure 4F, bath application of the same concentration of
4-CPG (50 µM) led to a significant reduction of
AreaF/F0 to 67% of control (n = 6; p < 0.05). This reduction was predominantly
caused by a slower rise and earlier decay of
[Ca2+]i (Fig. 4E).
The effect of 4-CPG was reversible in all neurons tested (Fig.
4E, wash out).
The results of the Ca2+ imaging studies led us to
conclude that weak tetanization paradigms that evoked a weak or
moderate [Ca2+]i response could be
affected by a mGluR class I antagonist. We thus investigated whether a
blockade of other Ca2+ sources during strong
tetanization, such as the entry of Ca2+ through
VDCCs, could enable class I mGluRs to affect LTP. To examine this
hypothesis, we coapplied the L-type VDCC antagonist nimodipine together
with the mGluR antagonists MCPG and 4-CPG during strong tetanization.
Nimodipine (10 µM; n = 8) applied on its
own during tetanization did not modify the potentiation in comparison
to control experiments (n = 6; data not shown). However, the coapplication of nimodipine (10 µM) and MCPG
(400 µM) led to a marked reduction of LTP (Fig.
5A). The impairment of LTP
became significant 150 min after tetanization and resulted in a
diminished potentiation of 127 ± 8% 240 min after LTP induction (n = 7) as compared with 179 ± 15% in the
control group (n = 7; p < 0.05).
Similar to the experiments with the weak tetanization, the initial
potentiation was unaffected, showing that post-tetanic potentiation was
not modified. The effects of 100 µM 4-CPG coapplied with
nimodipine (10 µM) (n = 7) resembled the
MCPG/nimodipine experiments. Although the initial potentiation was not
influenced, the 4-CPG/nimodipine group displayed a faster rundown of
potentiation, which became statistically distinguishable from controls
80 min after tetanus (Fig. 5B). After 240 min, the
potentiation had nearly declined to baseline (108 ± 12%) as
compared with controls (152 ± 7%).
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Figure 5.
Coapplication of mGluR class I antagonists and the
L-type calcium channel antagonist nimodipine impaired LTP evoked by a
strong tetanization protocol. A, MCPG (400 µM) affected the potentiation when nimodipine (10 µM) was coapplied. The reduction became significant 150 min after tetanization (p < 0.05;
n = 7). The control application of nimodipine alone
(n = 8) had no effect on LTP. B,
Similarly, coapplication of 4-CPG (100 µM) and nimodipine
resulted in a significant impairment of LTP starting 80 min after
tetanization (p < 0.05;
n = 7), whereas nimodipine by itself was not
effective (n = 8). C, Application of
thapsigargin (6 µM) had the same effect as mGluR class I
antagonists if coapplied with nimodipine (, p < 0.05; n = 7). The application of nimodipine (,
n = 7) and thapsigargin ( , n = 6) alone had no influence on LTP. See Figure 2 for further
explanation.
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Because the electrophysiological studies showed that nimodipine may
enable 4-CPG to affect LTP induced by strong tetanization, we tested
the coapplication of 4-CPG and nimodipine in confocal imaging
experiments. 4-CPG, bath-applied in the strong tetanization protocol (1 sec, 100 Hz), had no effect (Fig. 4G). However,
coapplication of 4-CPG with nimodipine (10 µM) caused a
significant reduction of AreaF/F0 to 78% of
control (n = 5; p < 0.05).
These results support our hypothesis that the efficiency of mGluR class
I antagonists depends on the level of
[Ca2+]i. During strong tetanization,
the Ca2+ influx through NMDARs is significantly
augmented by Ca2+ entering the neuron through L-type
VDCCs. The high Ca2+ level originating from these
two sources overrides the functional role of Ca2+
release from IP3-sensitive ICSs. If MCPG and 4-CPG block
release of Ca2+ from ICSs, then depleting these
stores by the Ca2+-ATPase inhibitor thapsigargin
should lead to a similar effect in the nimodipine/strong tetanization
paradigm.
As shown in Figure 5C, the application of thapsigargin (6 µM; n = 6) or nimodipine (10 µM; n = 7) had no independent effect on
robust LTP, which was induced by strong tetanization (initial values:
256 ± 12% and 255 ± 8%, respectively; 240 min values: 164 ± 10% and 159 ± 11%). However, coapplication of the
two drugs (n = 7) caused a severe impairment of
potentiation that declined from 228 ± 12% initially to 115 ± 4% after 240 min (controls: 256 ± 12% and 164 ± 10%,
respectively; p < 0.05).
Therefore, the mGluR antagonists MCPG and 4-CPG and the
Ca2+ store depletor thapsigargin only affected a
robust LTP if the intracellular Ca2+ level during
the tetanus was artificially lowered by blocking the
Ca2+ entry through L-type VDCCs.
| |
DISCUSSION |
The presented results demonstrate that the role of mGluRs in LTP
is contingent on the tetanization paradigm that is used. The stronger
the tetanization, the less potent were the mGluR antagonists MCPG and
4-CPG in affecting the time course of the resulting potentiation. MCPG
has been characterized as a competitive antagonist of class I and class
II mGluRs, whereas 4-CPG displays a selectivity toward class I mGluRs
and only weak activity on mGluRs of class II (Davies et al., 1995;
Sekiyama et al., 1996). Because in most of our experiments the results
obtained with the two antagonists were very similar, the effects of
these compounds on LTP may be assigned to an action on class I mGluRs.
This is consistent with the findings of other laboratories that
excitatory postsynaptic mGluR actions in the CA1 region are
mediated by activation of class I receptors (Davies et al., 1995;
Gereau and Conn, 1995) and that agonists of class I mGluRs may
facilitate the induction of LTP or induce a potentiation on their own
[McGuinness et al., 1991; Otani and Ben-Ari, 1991; Ben-Ari et al.,
1992; Bortolotto and Collingridge, 1992, 1995; Manahan-Vaughan and
Reymann, 1995, 1996; Breakwell et al., 1996; O'Leary and O'Connor,
1997 (but see Brown and Reymann, 1995)]. Both subtypes of class I
receptors, mGluR1 and mGluR5, are found in the CA1 subfield as shown by
in situ hybridization and immunohistochemical studies
[Petralia et al., 1997 (for further references, see Luján et
al., 1996)].
Our findings shed new light on the controversy concerning the
functional role of mGluRs in LTP and the contradictory data that have
been obtained with MCPG. If the studies that dealt with the action of
MCPG on hippocampal LTP are classified according to the type and
strength of tetanization applied, then the resulting picture is largely
consistent with the conclusions drawn from our experiments. Whereas in
all studies using a "strong" tetanization (theta-burst stimulation
or repetitive 100 Hz/1 sec protocols) MCPG failed to block LTP (Manzoni
et al., 1994; Selig et al., 1995; Thomas and O'Dell, 1995), a single
100 Hz stimulation of 1 sec duration appears to mark a critical
threshold where the involvement of mGluRs depends on certain (as yet
unknown) experimental conditions (Bashir et al., 1993; Chinestra et
al., 1993; Bortolotto et al., 1994; Thomas and O'Dell, 1995). In
contrast, all tetanization paradigms that used single 100 Hz protocols
<1 sec resulted in a potentiation that was dependent on a mGluR class
I activation. In our experiments, the potentiation became susceptible
to the action of MCPG and 4-CPG as soon the duration of the tetanus was reduced to 400 msec.
In our search for the basic mechanism that may underlie the
tetanization strength-dependent efficiency of MCPG and 4-CPG, we
focused on changes of the intracellular Ca2+ level
after activation of class I mGluRs during tetanization. It is generally
accepted that the induction of LTP in the CA1 area requires an
elevation of the free, intracellular Ca2+
concentration in the postsynaptic neuron (Lynch et al., 1983; Malenka
et al., 1988). In addition to Ca2+ influx through
NMDARs (Collingridge et al., 1983; Malenka, 1994), two other important
Ca2+ sources can feed the rise of
[Ca2+]i during tetanization:
Ca2+ influx through VDCCs and the release of
Ca2+ from IP3- and ryanodine-sensitive
ICSs (Thastrup et al., 1990; Berridge, 1993; Frenguelli et al.,
1996).
Activation of VDCCs appears to be critically involved in the generation
of LTP by strong tetanization at 200 Hz and higher frequencies (Grover
and Teyler, 1990). In contrast, the widely used strong 100 Hz paradigms
evoke a potentiation that contains a smaller, inconspicuous
VDCC-dependent component, as shown by Grover and Teyler (1994), and
confirmed in our experiments by the lack of significant effects of
nimodipine on potentiation.
Ca2+ release from ICSs (Thastrup et al., 1990;
Berridge, 1993) seems to play a decisive role in LTP induction under
certain conditions. Harvey and Collingridge (1992) reported a block of LTP if the selective Ca2+-ATPase inhibitor
thapsigargin was applied during tetanization, but not if given 30 min
afterward. In previous experiments in our laboratory, we found that
bath application of thapsigargin during tetanization did not affect a
robust LTP generated by a triple 100 Hz tetanus, but impaired a weaker
potentiation induced by a single 100 Hz train of 400 msec duration
(Behnisch and Reymann, 1995).
In this study, we did not see an effect of MCPG or 4-CPG on
potentiation induced by a strong 100 Hz protocol, which is in accordance with the findings of other groups (Chinestra et al., 1993;
Izumi and Zorumski, 1994; Manzoni et al., 1994; Thomas and O'Dell,
1995; Selig et al., 1995). However, coapplication of MCPG or 4-CPG with
nimodipine had detrimental consequences on potentiation. Thus,
inhibition of the Ca2+ influx through VDCCs during
tetanization did not result in overt changes of LTP, but the
potentiation became dependent on activation of class I mGluRs. Because
thapsigargin mimicked exactly the action of MCPG and 4-CPG in impairing
a robust LTP only when L-type VDCCs were additionally inhibited by
nimodipine, we concluded that both antagonists acted via an inhibition
of the IP3-mediated Ca2+-release
from ICSs (Thastrup et al., 1990; Berridge, 1993). These findings
indicated that the involvement of class I mGluRs in synaptic plasticity
depends on [Ca2+]i attained during
tetanization and the interaction between VDCCs and ICSs.
Although the confocal [Ca2+]i
measurements did not resolve the contribution of the different
Ca2+ sources to the tetanic
[Ca2+]i rise, they gave clear evidence
of a tight correlation between [Ca2+]i
and the strength of tetanization. In addition, they supported a
different functional role for mGluR-triggered Ca2+
release from IP3-sensitive ICSs during weak and strong
tetanic stimulation. Under our experimental conditions,
AreaF/F0 was not only monotonic but linearly
correlated to the pulse width and duration of tetanization. However,
the shape of [Ca2+]i responses and the
resulting AreaF/F0 might have been influenced by methodical constraints such as saturation of the
Ca2+ dye Calcium Green-1 (Kd 189 nM). The Ca2+ kinetics that we obtained
after tetanic stimulation of increasing duration and pulse width extend
the previous findings of Regehr and Tank (1992), who described
Ca2+ accumulations in response to tetanization (100 Hz for 1 sec) with increasing stimulation intensity. Malenka et al.
(1992) reported that the [Ca2+]i surge
within the initial 2 sec after onset of potentiation determines the
resulting type and the properties of plasticity. In our study, the
often used 100 Hz/1 sec stimulation led to intradendritic [Ca2+]i kinetics with a steep
increase, a maximum of ~1000 msec and an exponential decay resulting
in [Ca2+]i, which was still
elevated after 2 sec. The finding that 4-CPG attenuates the
tetanus-induced [Ca2+]i surge is
consistent with the studies of Frenguelli et al. (1993), which
described a similar effect for MCPG, and in accordance with Alford et
al. (1993), who reported that blockade of Ca2+
release from ICSs may cause a considerable reduction of
[Ca2+]i in CA1 pyramidal neurons.
However, in our hands, 4-CPG reduced only the
[Ca2+]i elevation induced by weak but
not by strong tetanization.
Putting all of these facts together, we hypothesize that the three main
Ca2+ sources interfere with each other during
LTP induction, as schematically outlined in Figure
6. During weak tetanization (Fig.
6A1), the characteristics of the attained
depolarization do not allow the L-type VDCCs to contribute
significantly to the Ca2+ influx required for LTP
induction. The Ca2+ entry is therefore accomplished
predominantly via NMDARs. The moderate intracellular
Ca2+ level and IP3 liberated by
activation of class I mGluRs trigger the release of
Ca2+ from IP3-sensitive stores resulting
in an amplification and prolongation of the Ca2+
signal beyond the threshold for LTP induction, as supported by computational studies (Schiegg et al., 1995).
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|
Figure 6.
Scheme of the role of the three main
Ca2+ sources during LTP induction in dependence of
the tetanization strength. The final
[Ca2+]i necessary for induction of LTP
is determined by two factors, the NMDARs and an additional source
provided by either VDCCs or the Ca2+ release from
ICSs after activation of class I mGluRs. Top scheme,
A1, During a weak, single tetanization the rise of
[Ca2+]i is fed by the activation of
NMDARs and class I mGluRs, whereas the contribution of L-type VDCCs is
negligible under these conditions. Thus, application of class I
antagonists causes an impairment of LTP (A2).
Bottom scheme, B1, A strong tetanization
paradigm leads to a sustained depolarization enabling the
Ca2+ entry via NMDARs and VDCCs, as well as to the
release of Ca2+ from ICSs.
B2, The additional Ca2+ that
is provided by the release from ICSs via liberation of IP3
on class I mGluR activation is not required for LTP induction.
B3, Blockade of VDCCs is counterbalanced by the
class I mGluR-triggered Ca2+ release from ICSs.
B4, Concomitant inhibition of class I mGluRs and
VDCCs results in a decremental potentiation.
|
|
In contrast, during strong tetanization (Fig.
6B1) leading to a sustained
depolarization, the contribution of VDCCs to the [Ca2+]i surge is increased, i.e.,
Ca2+ enters the neuron via NMDARs and VDCCs. The
corresponding high [Ca2+]i may
interfere via two different mechanisms with the class I-triggered Ca2+ release. (1) The high
[Ca2+]i could functionally override
the contribution of the surplus Ca2+ from ICSs,
i.e., the threshold for LTP induction (Lisman, 1989; Artola and Singer,
1993; Cummings et al., 1996; Neveu and Zucker, 1996; Tsumoto and
Yasuda, 1996) can be achieved solely by activation of NMDARs and VDCCs.
(2) The high cytosolic Ca2+ concentration can
decrease the Ca2+ release from
IP3-sensitive stores because of the bell-shaped Ca2+ sensitivity of IP3 channels
(Bootman and Berridge, 1995).
The findings of the present study and the available experimental
evidence lead us to hypothesize that class I mGluRs have a particular
function in LTP. During weak and moderate tetanization, they amplify
the initial [Ca2+]i surge that
originates from Ca2+ influx through NMDARs, beyond
the threshold for LTP induction; i.e., by instigating the
Ca2+ release from IP3-sensitive ICSs
they enable an NMDA-dependent input-specific LTP. Therefore, at
moderate levels of synaptic activation, class I mGluRs may function as
threshold boosters in input-specific Hebb-type plasticity.
| |
FOOTNOTES |
Received Dec. 19, 1997; revised May 14, 1998; accepted May 27, 1998.
This research was supported by the Deutsche Forschungsgemeinschaft
Sonderforschungsbereich 426. We thank Dr. Denise Manahan-Vaughan and Dr. Ritchie Brown for critical comments on this manuscript, and Ms.
Katrin Böhm for excellent technical assistance.
Correspondence should be addressed to Detlef Balschun, Leibniz
Institute for Neurobiology, Department of Neurophysiology, P.O. Box
1860, D-39008 Magdeburg, Germany.
| |
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Top
Abstract
Introduction
