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The Journal of Neuroscience, November 15, 2000, 20(22):8572-8576
Requirement of Translation But Not Transcription for the
Maintenance of Long-Term Depression in the CA1 Region of Freely
Moving Rats
Denise
Manahan-Vaughan1,
Alexander
Kulla1, and
J.
Uwe
Frey2
1 Johannes Mueller Institute for Physiology, Synaptic
Plasticity Research Group, Humboldt University Medical Faculty
(Charité), D-10115 Berlin, Germany, and 2 Leibniz
Institute for Neurobiology, Department of Neurophysiology, D-39008
Magdeburg, Germany
 |
ABSTRACT |
Hippocampal long-term depression (LTD) comprises a persistent
reduction in synaptic strength that can be induced in the CA1 region by
repeated low-frequency stimulation (LFS). Previous studies have
demonstrated that hippocampal long-term potentiation requires de
novo protein synthesis. Whether hippocampal LTD is also protein synthesis-dependent is not known. In this study, we investigated if the
previous administration of translation inhibitors (anisomycin or
emetine) or a transcription inhibitor (actinomycin-D) influenced the
profile of LTD in freely moving adult Wistar rats. Seven- to 8-week-old
animals underwent chronic implantation of a recording electrode in the
CA1 stratum radiatum and a stimulation electrode in the Schaffer
collateral/commissural fiber pathway. A cannula was implanted in the
ipsilateral cerebral ventricle to enable drug administration.
Experiments were commenced 10 d after the implantation procedure.
Immediately after application of LFS (1 Hz, 900 pulses) robust LTD was
seen that persisted for >8 hr in control animals. Application of
anisomycin (240 µg/5 µl) emetine (240 µg/5 µl) before LFS
prevented the expression of LTD or ~4.5 hr after LFS. Previous
administration of actinomycin D (72 µg/12 µl) had no effect on the
expression of LTD. None of the compounds elicited significant effects
on basal synaptic transmission when administered in the absence of LFS.
These data suggest that LTD in the CA1 region in vivo is
protein synthesis-dependent. Furthermore, persistent LTD can be
established through the translation of existing mRNA, whereas de
novo mRNA transcription does not appear to be necessary.
Key words:
actinomycin D; anisomycin; long-term depression; Wistar; hippocampus; protein synthesis; mRNA; transcription; translation
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INTRODUCTION |
Hippocampal long-term depression
(LTD) comprises a persistent functional decrease in synaptic
transmission that occurs as a consequence of patterned stimulation of
afferent fibers (Bear and Malenka, 1994 ). As is the case with
hippocampal long-term potentiation (LTP), it is dependent on
intracellular calcium mobilization, through for example, calcium entry
via NMDA receptor channels (Dudek and Bear, 1992; Mulkey and Malenka,
1992) and activation of metabotropic glutamate receptors (mGluRs)
(Huang et al., 1997; Manahan-Vaughan, 1997). The relative intracellular
concentration of calcium is likely to be a crucial determinant of the
form of synaptic plasticity subsequently expressed (Artola and Singer, 1993).
It has been suggested that the mechanisms underlying LTD expression, in
conjunction with the mechanisms of LTP, are responsible for information
storage by the hippocampus (Bear, 1996). Furthermore, hippocampal LTP
and LTD may be associated with specific forms of explicit memory
in the cerebral cortex. It has been demonstrated that distinct
hippocampus-associated memory storage occurs in phases (Grecksch and
Matthies, 1980; Grecksch et al., 1980). This has also shown to be
the case with regard to hippocampal LTP, in which late LTP can be
dissociated from short-term potentiation (STP) (which lasts for
minutes) and early LTP (which lasts for up to 4 hr) by means of protein
synthesis inhibitors or inhibitors of protein kinase A (Krug et al.,
1984; Frey et al., 1988, 1993, 1996; Otani et al., 1989; Matthies et
al., 1990). Recently, hippocampal LTD, which endures for many days, has
been demonstrated in freely moving rats (Manahan-Vaughan and
Braunewell, 1999). This form of LTD also exists in phases: an NMDA
receptor-dependent phase of short-term depression (STD), which lasts
for ~1 hr, and an mGluR-dependent phase, which becomes evident
immediately after the NMDA receptor phase and which might resemble the
stage of early LTP (Manahan-Vaughan, 1997).
Information storage in the form of a long-term reduction in synaptic
plasticity may be accompanied by protein synthesis-dependent synaptic
modifications. First, indications that the maintenance of LTD may
depend on protein synthesis came from studies in the cerebellum, in
which the application of protein synthesis inhibitors prevented late
LTD (Linden, 1996; Levenes et al., 1998). Whether hippocampal LTD also
has a protein synthesis-dependent phase has not been established to
date. This study therefore set about to examine whether inhibitors of
mRNA translation and transcription influence the expression of
hippocampal LTD in freely moving rats.
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MATERIALS AND METHODS |
Surgical preparation. Seven- to 8-week-old male
Wistar rats were prepared as described previously (Manahan-Vaughan,
1997). Briefly, under sodium pentobarbitone anesthesia (Nembutal; 40 mg/kg, i.p.), animals underwent implantation of a monopolar recording and a bipolar stimulating electrode (made from 0.1 mm diameter Teflon-coated stainless steel wire). A drill hole was made
(1-mm-diameter) for the recording electrode (2.8 mm posterior to
bregma, 1.8 mm lateral to the midline), and a second drill hole (1 mm
diameter, 3.1 mm posterior to bregma, 3.1 mm lateral to the midline)
was made for the stimulating electrodes (coordinates based on Paxinos and Watson, 1986). The dura was pierced through both holes, and the
recording and stimulating electrodes were lowered into the CA1 stratum
radiatum and the Schaffer collaterals, respectively. Recordings of
evoked field potentials via the implanted electrodes were taken
throughout surgery. A cannula was implanted in the lateral cerebral
ventricle (0.08 mm posterior to bregma; midline: 1.6 mm lateral to the
midline). Once verification of the location of the electrodes was
complete, the entire assembly was sealed and fixed to the skull with
dental acrylic (Paladur; Heraeus Kulzer, GmbH, Wehrheim, Germany). The
animals were allowed 10 d to recover from surgery before
experiments were conducted. Twenty-four hours before the commencement
of the experiments, animals were placed in the recording chamber with
ad libitum access to food and water, to allow
familiarization to occur. Throughout the experiments the animals could
move freely within the recording chamber (40 × 40 × 40 cm),
as the implanted electrodes were connected by a flexible cable and
swivel connector to the stimulation unit and amplifier. Aside from the
insertion of the connector cable and injection cannula at the start of
the experiment, disturbance of the animals was kept to an absolute
minimum. Throughout the experiments the electroencephalogram of each
animal was continuously monitored.
Measurement of evoked potentials. The field EPSP (fEPSP)
slope was used as a measure of excitatory synaptic transmission in the
CA1 region. To obtain these measurements, an evoked response was
generated in the stratum radiatum by stimulating at low frequency (0.025 Hz) with single biphasic square wave pulses of 0.1 msec duration
per half wave, generated by a constant current isolation unit. For each
time point measured during the experiments, five records of evoked
responses were averaged. fEPSP was measured as the maximal slope
through the five steepest points obtained on the first negative
deflection of the potential. By means of input-output curve
determination, the maximum fEPSP was found, and during experiments all
potentials used as baseline criteria were evoked at a stimulus
intensity that produced 40% of this maximum. LTD was induced by
low-frequency stimulation (LFS) at 1 Hz (900 pulses). Only fEPSPs in
which 40% of the input-output maximum could be evoked using a
stimulation intensity of  150 µA were used for this study. If the
fEPSPs fulfilled this criterion, LTD was consistently evoked throughout
the experiments. Ambient conditions were kept constant to prevent
environmental influences on behavioral state that might affect the LTD
expressed (Manahan-Vaughan and Braunewell, 1999; Manahan-Vaughan,
2000a).
Compounds and drug treatment. For injection, anisomycin and
emetine (2.4 mg; Sigma-Aldrich) were first dissolved in 15 µl of HCl
solution (1 N) and then treated with 1 N NaOH to create a pH of 7.0. The solutions were subsequently made up to a 50 µl volume with 0.9%
sodium chloride. The animal was injected with 5 µl of this solution
(240 µg) over a 6 min period via a Hamilton syringe. Actinomycin-D
(Sigma-Aldrich) was fully dissolved in 0.9% sodium chloride. A pH of
7.0 was established using 1 N NaOH. The total amount injected was 72 µg/12 µl over a 6 min injection duration. Throughout the
experiments, drugs or vehicle were applied into the lateral cerebral
ventricle via an injection cannula that was inserted through the
surgically implanted outer cannula. In all experiments, drug or vehicle
injection was administered after the observation of basal synaptic
transmission for 30 min. Two hours later LFS was applied. Evoked
responses were then monitored for a further 8 hr. In case of control
experiments in which no LFS was given, evoked responses were monitored
for a total of 10 hr after drug or vehicle injection.
Data analysis. The baseline fEPSP data were obtained by
averaging the response to stimulation of the Schaffer collaterals, to
obtain five sweeps at 40 sec intervals, every 5 min over a period of 30 min. Drug or vehicle injections were then applied, and three further
measurements at 5 min intervals were taken, followed by recordings at
15 min intervals for 2 hr. At this point LFS was given, and three
measurements at 5 min intervals were then taken and followed by
recordings at 15 min intervals for 8 hr. The same protocol for
observation of evoked potentials was followed in which no LFS was
given. The data were then expressed as mean percentage of preinjection
baseline fEPSP reading ± SEM. Statistical significance was
estimated using the Mann-Whitney U test. The probability
level interpreted as statistically significant was *p < 0.05.
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RESULTS |
Hippocampal long-term depression in freely moving rats requires
protein translation
When LFS (900 pulses at 1 Hz) was applied via the Schaffer
collateral- commissural pathway to the stratum radiatum of the CA1
region, an LTD of the fEPSP was generated that was still present 8 hr
after LFS was given (data not shown). No change in the profile of LTD
was seen when a vehicle injection was applied 2 hr before LFS via a
cannula implanted in the lateral cerebral ventricle (n = 6; Fig. 1A). The
fEPSP 5 min after LFS was 42 ± 6% of preinjection fEPSP baseline
values, and LTD was still present after 8 hr. This type of LTD has been
shown to persist of over 7 d in this rat strain (Manahan-Vaughan
and Braunewell, 1999).
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Figure 1.
LTD in the CA1 region in vivo is
dependent on protein translation. A, A low-frequency
train (LFS) in the presence of a vehicle injection
(n = 6) results in a robust LTD that persists for
>8 hr. Injection of the protein translation inhibitors anisomycin (240 µg/5 µl; n = 10) or emetine (240 µg/5 µl;
n = 7) 2 hr before LFS completely inhibits the
expression of LTD from ~4.5 hr after LFS. B,
Anisomycin (240 µg/5 µl; n = 6) or emetine (240 µg/5 µl; n = 7) have no effect on basal
synaptic transmission compared to vehicle-injected controls
(n = 6). C, Original analog traces
showing evoked responses in the CA1 region at three time points:
preinjection, t = 5 min and t = 8 hr after LFS, in (i) a vehicle-injected animal
and (ii) an animal injected with anisomycin (240 µg/5
µl). Calibration: 5 msec, 5 mV. Line breaks indicate
change in time scale.
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The involvement of protein translation in the induction of hippocampal
LTD in vivo was examined using the reversible translation inhibitor anisomycin, and emetine. When anisomycin was applied 2 hr
before LFS, in a concentration that effectively blocked LTP in
vivo (240 µg/5 µl injection volume; data not shown), a
significant inhibition of LTD occurred (Fig. 1A).
Five minutes after LFS, the fEPSP in the anisomycin group was 48.8 ± 4.54% of preinjection fEPSP baseline values (n = 10). This depression was maintained until t = 270 min
after LFS when a significant recovery of fEPSP values in the anisomycin
group was noted. Thus, at t = 270 min after LFS, the
values of the control group were statistically different when compared
with anisomycin-treated animals (60.8 ± 5.99% vs 91.7 ± 9.52% (U test, p < 0.05).
The same concentration of anisomycin (240 µg/5 µl injection volume;
n = 6) had no significant effect on hippocampal basal synaptic transmission when compared to vehicle-treated control animals
(n = 6; Fig. 1B).
When emetine was administered 2 hr before LFS, in a concentration which
was reported to significantly block hippocampal LTP in vivo
(240 µg; Otani et al., 1989), a significant inhibition of LTD
occurred that was similar to that seen with anisomycin (Fig.
1A). Five minutes after LFS, the fEPSP in the emetine
group was 54.9 ± 3.74% of pre-injection fEPSP baseline values
(n = 7). This depression was maintained until
t = 255 min after LFS when a significant recovery of
fEPSP values in the emetine group was observed. Thus, at
t = 255 min after LFS, the values of the
emetine-treated group (90.8 ± 3.77%) were statistically
different when compared to controls (67.8 ± 4.64%;
n = 6; U test, p < 0.05).
Emetine (240 µg/5 µl injection volume; n = 7) had
no significant effect, however, on hippocampal basal synaptic
transmission when compared to vehicle-treated control animals
(n = 6; Fig. 1B).
Hippocampal long-term depression in freely moving rats
does not require transcription
To investigate the involvement of transcription in hippocampal LTD
in vivo, the transcription inhibitor actinomycin-D was used.
This concentration significantly inhibits hippocampal late LTP in
vivo with regard to population spike amplitude (whereas fEPSP
slope remains largely unchanged) (Frey et al., 1996). Furthermore, Otani et al. (1989) demonstrated a 95% inhibition of hippocampal mRNA synthesis when 60 µg of actinomycin-D was injected into the lateral cerebral ventricle. Thus, an effective inhibition of
transcription can be expected at the higher dose, 72 µg, used in our study.
When actinomycin-D (72 µg/12 µl injection volume) was administered
2 hr before LFS, no significant modification of the profile of LTD
occurred (Fig. 2A).
Five minutes after LFS fEPSP values were 38.8 ± 6.47% of
preinjection fEPSP baseline values in controls (n = 6)
and 46.3 ± 6.52% in actinomycin-D-treated animals
(n = 6). Eight hours after administration of LFS, fEPSP
values were 59.5 ± 3.22% and 61.8 ± 4.23% in vehicle- and
actinomycin-treated animals, respectively.
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Figure 2.
LTD in the CA1 region in vivo is
not dependent on transcription. A, A low-frequency train
(LFS) in the presence of vehicle (n = 6) results in a robust LTD that persists for >8 hr. Injection of the
protein transcription inhibitor actinomycin-D (72 µg/12 µl;
n = 6) 2 hr before LFS has no effect on the
expression of LTD compared to vehicle-treated animals.
B, Actinomycin-D (72 µg/12 µl; n = 6) has no effect on basal synaptic transmission compared to
vehicle-injected controls (n = 6).
C, Original analog traces showing evoked responses in
the CA1 region at three time points: preinjection,
t = 5 min and t = 8 hr after
LFS, in (i) a vehicle-injected animal and
(ii) an animal injected with actinomycin-D (72 µg/12
µl; n = 6). Calibration: 5 msec, 5 mV.
Line breaks indicate change in time scale.
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The same concentration of actinomycin (72 µg/12 µl injection
volume) had no effect on hippocampal basal synaptic transmission when
compared to vehicle-treated control animals (Fig.
2B).
| |
DISCUSSION |
The data from this study support the hypothesis that LTD in the
CA1 region of freely moving rats is dependent on protein synthesis. Furthermore, the protein synthesis concerned appears to be performed using existing mRNA, whereas transcription of new mRNA does not appear
to be necessary for the time period investigated (8 hr). The
possibility that the transcription and translation inhibitors used had
toxic effects within the experimental time course studied can be
minimized because no significant effect on basal synaptic transmission
elicited by test-pulse stimulation was noted for either anisomycin,
emetine, or actinomycin-D. However, subtle unspecific effects, which
are not expressed as immediate changes of electrophysiological
responses, cannot be excluded.
Interestingly, as is the case with hippocampal LTP, LTD appears to be
characterized by distinct phases that mechanistically mirror those
described for memory formation in mammals (Matthies et al., 1990).
Thus, together with the previously described NMDA receptor and
mGluR-dependent STD (Dudek and Bear 1992; Mulkey and Malenka, 1992;
Huang et al., 1997; Manahan-Vaughan, 1997, 1998, 2000b), which is
associated with subsequent activation of calcium calmodulin kinase II,
activation of calcineurin, and disinhibition of protein phosphatase 1 (Bear and Malenka, 1994), hippocampal LTD is also accompanied by a
protein synthesis-dependent phase that becomes evident ~4 hr after
LFS. Given NMDA receptor-dependent kinase regulation (Norman et al.,
2000) and the mGluR-dependent involvement of protein kinase A, C
(Kameyama et al., 1998; Huang et al., 1999a,b), and G (Wu et al., 1998)
in hippocampal LTD, together with the reported requirement of kinases
such as protein kinase A for protein synthesis in other forms of
hippocampal plasticity (Frey et al., 1993; Nayak et al., 1998), it is
quite possible that these LTD phases are interrelated. Recently, it
was shown that the chemical induction of CA1 LTD in vitro by
application of a group I mGluR agonist depends on protein synthesis in
the form of mRNA translation (Huber et al., 2000). LFS-induced CA1 LTD
in vivo is dependent on mGluR activation (Manahan-Vaughan, 1997), suggesting a further link in these processes.
Hippocampal LTD, as determined by changes in fEPSP, i.e., the synaptic
response, does not appear to require de novo RNA synthesis. Thus, application of actinomycin-D did not alter the profile of LTD
subsequently expressed. Within the present study a comparison was not
made with the effectiveness of actinomycin-D in blocking CA1 LTP
in vivo. Thus, one cannot rule out the possibility that the
failure of actinomycin-D to block LTD arose as a result of insufficient
drug concentration. However, Otani et al. (1989) reported a 95%
inhibition of hippocampal mRNA synthesis when 60 µg of actinomycin-D
was injected into the rat lateral cerebral ventricle. Thus, an
effective inhibition of transcription should be expected at the higher
dose, 72 µg, used in the present study. Interestingly, our data are
in accordance with our earlier report showing that LTP in the CA1
region, if determined by changes in fEPSP responses, seems not to
require transcription during the first 8 hr after LTP induction (Frey
et al., 1996). This finding indicates that LTD and LTP may use common
mechanisms for consolidation. However, the latter results are in
contrast to similar experiments in the hippocampal CA1 in which the
application of mRNA synthesis inhibitors blocked the induction of late
LTP when also measured as changes in fEPSP responses (Nguyen et al.,
1994). These contradictory findings could be attributable to
nonspecific effects of actinomycin-D caused by the presence of the drug
during induction of LTP in the latter in vitro experiments.
The finding that transcription-dependent protein synthesis is not
required for LTD in vivo suggests, however, that mRNA that is already present within the dendrite of the activated synapses is
used to encode the proteins that enable persistent LTD. Dendritic protein synthesis has been described for hippocampal neurons (Steward, 1994, 1997). Furthermore, mRNA has been localized at the base of
hippocampal dendritic spines (Steward and Levy, 1982; Kleiman et
al., 1990; Martone et al., 1996; Tiedge and Brosus, 1996). Recently,
chemical induction of CA1 LTD via a group I metabotropic glutamate
receptor agonist was shown to depend on dendritic mRNA (Huber et al.,
2000). Thus, the possibility that hippocampal LTD uses local mRNA for
protein synthesis exists. Indeed, mRNA for proteins that are postulated
to play a role in LTD have been identified near dendritic spines, such
as certain subunits for the glutamate receptor and  CAMkinase II
(Steward, 1997).
It cannot be ruled out of course, that proteins essential for LTD are
synthesized either in the soma and then transported along the dendrite
to the activated target synapses, or synthesized in specific dendritic
compartments that are relatively far away from the activated synapse. A
corollary of this is the possibility that a synaptic tag (Frey and
Morris, 1997, 1998) is involved in the consolidation of LTD. It has
already been demonstrated for hippocampal LTP that synapses activated
by tetanic stimulation can recruit proteins, whose synthesis has
been initiated at other sites within the neuron, and thereby enable
stabilization of long-term potentiation. A similar mechanism may be
used in LTD. Translation of mRNA at the soma could then result in
protein transport through the neuron that would then be sequestered by
the synapses that were activated by LFS.
Recently it was demonstrated that hippocampal LTD may be associated
with novelty acquisition and recognition in rats (Manahan-Vaughan and
Braunewell, 1999), this finding adds weight to earlier postulations that hippocampal LTD may be associated with learning and memory in
mammals (Bear, 1996; Bear and Abraham, 1996). Given existing evidence
for a role for protein synthesis in hippocampus-based learning
phenomena (Grecksch and Matthies, 1980; Grecksch et al., 1980; Mizumori
et al., 1985; Quevedo et al., 1999), these findings, together with the
current data supporting the involvement of protein synthesis in LTD
consolidation, prompt a revision in current thinking that favors LTP as
the cellular basis of learning and memory. Rather it may be the case
that both forms of synaptic plasticity serve different forms of
learning and memory.
In conclusion, the current data show that, as is the case with LTP, LTD
in the CA1 region of freely moving rats is protein synthesis-dependent.
Transcription of new mRNA is apparently not necessary for LTD
consolidation within the first 8 hr after its induction, rather
existing mRNA is translated to create the proteins required. These data
offer the first evidence to demonstrate a role for protein synthesis in
hippocampal LTD, and given the role of protein synthesis in learning
and memory phenomena, point to a significant involvement of this form
of synaptic plasticity in information storage in the mammalian brain.
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FOOTNOTES |
Received April 25, 2000; revised Aug. 25, 2000; accepted Aug. 29, 2000.
This work was supported by Deutsche Forschungsgemeinschaft Grant SFB
515/B8 to D.M.-V. We acknowledge the back-up support of Ms. S. Vieweg,
Dr. K.-H Braunewell, and Ms. K. Schuetz.
Correspondence should be addressed to Dr. Denise Manahan-Vaughan,
Johannes Mueller Institute for Physiology, Synaptic Plasticity Research
Group, Humboldt University Medical Faculty (Charité), D-10115
Berlin, Germany. E-mail: denise.manahan-vaughan{at}charite.de.
| |
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