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The Journal of Neuroscience, March 15, 1999, 19(6):2122-2130
Brain-Derived Neurotrophic Factor Prevents Low-Frequency
Inputs from Inducing Long-Term Depression in the Developing Visual
Cortex
Shuichiro
Kinoshita1,
Hiroki
Yasuda1,
Nobuaki
Taniguchi1,
Ritsuko
Katoh-Semba2,
Hiroshi
Hatanaka3, and
Tadaharu
Tsumoto1
1 Department of Neurophysiology, Biomedical Research
Center, Osaka University Medical School, Suita, 565-0871 Japan,
2 Institute for Developmental Research, Aichi Human Service
Center, Kasugai, Aichi 480-0392 Japan, and 3 Division of
Protein Biosynthesis, Institute for Protein Research, Osaka University,
Suita, 565-0871 Japan
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ABSTRACT |
Brain-derived neurotrophic factor (BDNF) is reported to enhance
synaptic transmission and to play a role in long-term potentiation in
hippocampus and neocortex. If so, a shortage or blockade of BDNF might
lead to another form of synaptic plasticity, long-term depression
(LTD). To test this possibility and to elucidate mechanisms if it is
the case, EPSCs evoked by test stimulation of layer IV were
recorded from layer II/III neurons in visual cortical slices of young
rats in the whole-cell voltage-clamp mode. LTD was induced by
low-frequency stimulation (LFS) at 1 Hz for 10-15 min if each pulse of
the LFS was paired with depolarization of neurons to  30 mV but was
not induced if their membrane potentials were kept at 70 mV. Such an
LTD was blocked by exogenously applied BDNF, probably through
presynaptic mechanisms. Suppression of endogenous BDNF activity by the
anti-BDNF antibody or an inhibitor for BDNF receptors made otherwise
ineffective stimuli (LFS without postsynaptic depolarization) effective
for LTD induction, suggesting that endogenous BDNF may prevent
low-frequency inputs from inducing LTD in the developing visual cortex.
Key words:
long-term depression; brain-derived neurotrophic factor; long-term potentiation; synaptic plasticity; visual cortex; development
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INTRODUCTION |
Neurotrophins, the family of nerve
growth factor (NGF), have been reported to enhance excitatory synaptic
transmission (Lohof et al., 1993 ; Le mann et al., 1994; Kang and
Schuman, 1995; Levine et al., 1995; Stoop and Poo, 1996; Akaneya et
al., 1997; Carmignoto et al., 1997; Scharfman, 1997) or to suppress
inhibitory transmission (Kim et al., 1994; Tanaka et al., 1997) and
further to play a role in a form of synaptic plasticity, long-term
potentiation (LTP), in the hippocampus and developing visual cortex
(Castrén et al., 1992; Patterson et al., 1992; Kang and Schuman,
1995; Korte et al., 1995; Figurov et al., 1996; Patterson et al., 1996; Akaneya et al., 1997). In field potential recordings from the visual
cortex of young rats, it was reported that one of the neurotrophins, brain-derived neurotrophic factor (BDNF), blocks the induction of
another form of synaptic plasticity, long-term depression (LTD), which
otherwise is induced by low-frequency stimulation (LFS) at 1 Hz for
10-15 min of afferents (Akaneya et al., 1996; Huber et al., 1998).
Such an action of BDNF was suggested to play a role in consolidation or
protection of immature synapses (Akaneya et al., 1996), which are known
to be easily depressed by low-frequency, repetitive inputs (Dudek and
Bear, 1993; Dudek and Friedlander, 1996). It is not yet known, however,
whether the site of the LTD-blocking action of exogenously applied BDNF
is presynaptic or postsynaptic, and more importantly whether endogenous
BDNF actually plays such a role in the developing visual cortex.
To examine these questions we recorded EPSCs with whole-cell voltage
clamping of layer II/III neurons in visual cortical slices of young
rats and found that LTD was induced only when LFS was paired with a
certain level of postsynaptic depolarization, and that BDNF may exert
its action on presynaptic sites where LTD is reported to be expressed
in visual cortex (Torii et al., 1997). Furthermore, the inhibition of
activity of endogenous BDNF with the anti-BDNF antibody made the
otherwise ineffective LFS effective to induce LTD. This result suggests
that endogenous BDNF may prevent low-frequency inputs from inducing LTD
and thus play a crucial role in consolidation of immature synapses,
which are bombarded by inputs at various frequencies from retinae in
the developing visual cortex (Shatz, 1990).
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MATERIALS AND METHODS |
Preparation of slices. Sprague Dawley rats, aged from
13 to 18 postnatal days, were deeply anesthetized with ketamine (30 mg/kg, i.p.), followed by cervical dislocation. Coronal slices of
visual cortex (300 µm thickness) were cut using a rotor slicer (DTY7000, Dosaka, Japan). Procedures for maintaining the slices were
essentially the same as described previously (Akaneya et al., 1997). In
short, slices were submerged in a stream of the perfusion medium at the
rate of 200 ml/h. The composition of incubation and perfusion medium of
the slices was as follows (in mM): NaCl 124, KCl 5, KH2PO4 1.2, MgSO4 1.3, CaCl2 2.4, NaHCO3 26, and glucose 10. All of
the recordings were performed at 30-31°C.
Stimulation of afferents and recording of synaptic currents.
A bipolar stimulating electrode was placed in layer IV of the cortex.
EPSCs evoked by test stimulation of layer IV were recorded from
pyramidal cell-like neurons in layer II/III of the cortex through
whole-cell patch-clamp electrodes (Yoshimura and Tsumoto, 1994). These
neurons were identified visually using an upright microscope with
Nomarski optics (Axioscope FS, Zeiss, Germany). Patch pipettes
(resistance, 8-10 M ) were filled with a solution containing (in
mM): 130 potassium gluconate, 10 KCl, 10 HEPES, 3 MgATP,
0.5 Na2GTP, and adjusted to pH 7.2 by KOH. The osmolarity of the solution was 270 mOsm. Visually identified neurons were voltage-clamped at 70 mV with a patch-clamp amplifier (Axoclamp 2B,
Axon Instruments, Foster City, CA). The fast transient capacitive currents for recording electrodes were canceled. The series resistance was <30 M. Data were digitized at a rate of 10 kHz and fed into an
IBM-PC clone computer for analysis. Synaptic currents were filtered at
1 kHz. These data were analyzed mainly with pClamp or AxoScope software
(Axon Instruments).
Test pulses of 0.1 msec width were delivered at 0.1 Hz, and the
stimulus intensity was adjusted usually to 1.2-1.5 times the threshold
for EPSCs. The intensity of test shocks was usually 1.5-3.0 V for 0.1 msec duration. After having confirmed that test shocks given to layer
IV at 0.1 Hz induced EPSCs with almost constant amplitude for 10 min,
LFS at 1 Hz was applied to the same site in layer IV for 10 or 15 min.
The width of each pulse of LFS and its voltage were the same as those
of test shocks. EPSCs were further observed for at least 20 min after
cessation of the LFS. To see a possible dependence of LTD induction on
postsynaptic membrane potential, each pulse of the LFS was paired with
depolarization of recorded neurons to 30 or 50 mV for 100 msec
(Yoshimura and Tsumoto, 1994). This depolarization was initiated 10 msec before each shock of LFS. The pairing procedure was performed at 1 Hz for 10 or 15 min. To evaluate effects of LFS on EPSCs in various conditions quantitatively, the means of peak amplitude and initial slope of EPSCs for 10 min before LFS were taken as control value. The
slope was calculated using the value for 10-60% of the initial, falling phase of EPSCs.
In most of the experiments, recombinant human BDNF (provided from
Sumitomo Pharmaceutical Co., Ltd., Japan) or K252a (provided from Kyowa
Hakko Co., Ltd., Japan) was applied to slices through the perfusion
medium 20 min before the initiation of LFS. BDNF was prepared at the
concentration of 500 µg/ml containing 0.1% bovine serum albumin in
undiluted Ca2+-, Mg2+-free
PBS. Then it was diluted to be 20 ng/ml with the perfusion medium just before recordings. For application of K252a, it was prepared to be the final concentration of 200 or 300 nM
with dimethyl sulfoxide (DMSO) as vehicle, of which the final
concentration was 0.01% (v/v). In the experiments in which K252b was
injected into cortical neurons, it was prepared with DMSO and patch
pipette solution. The concentrations of K252b and DMSO in pipettes were 200 nM and 0.01% (v/v), respectively. In part of the
experiments, K252b was mixed with rhodamine (15 µM) to
see the spread of K252b into neurons with the fluorescent microscope
(Axioscope FS). To prevent a possible adhesion of the neurotrophins to
the wall of the perfusion system, the inner walls of the reservoir,
recording chamber, and tubes connecting them were coated by
silicone 2-3 d before recording.
Preparation and purification of the anti-BDNF antibody.
BDNF-specific antibodies were prepared as described previously
(Katoh-Semba et al., 1997). In short, BDNF (3 ng/1.5 ml) was treated
with formalin (3 µl) at room temperature for 30 min, and then the
excess formalin was inactivated with Tris-HCl, pH 8.0. Polyclonal
antibodies against BDNF were raised by immunizing rabbits with the
formalin-treated BDNF. The BDNF-specific IgGs were purified from the
antiserum on a column of Sepharose CL-4B coupled with recombinant human BDNF. The specificity of the resultant polyclonal antibodies against BDNF was checked by the immunoblotting procedure as described previously (Katoh-Semba et al., 1997).
Evaluation of biological activity of the anti-BDNF antibody in
neuronal cultures. Biological activity of the polyclonal antibody was assayed in dissociated primary cultures of basal forebrain neurons
from embryonic rats, as described previously (Hatanaka and Tsukui,
1986). Briefly, tissue fragments of the basal forebrain area containing
the septum and the vertical limb of the diagonal band were dissected
out from embryonic day 18 rats (Wistar ST, Shizuoka, Japan), digested
with papain (90 U; Worthington, Freehold, NJ) twice for 15 min each
time at 37°C, and then resuspended in the medium containing 5% (v/v)
precolostrum newborn calf serum (Mitsubishi Kasei), 5% (v/v) horse
serum (Life Technologies, Gaithersburg, MD), 1% (v/v) rat serum, and
89% (v/v) DF medium (1:1 mixture of DME and Ham's F12 medium
containing 15 mM HEPES buffer, pH 7.4, 30 nM
selenium, and 1.9 mg/ml sodium bicarbonate). Cells were then
dissociated by gentle drawing through plastic tips of two sizes (1.2 mm
followed by 0.8 mm in diameter). Cells were resuspended in the above
serum-containing medium and seeded onto polyethyleneimine-coated
48-well plates (0.65 cm2/well; Sumitomo Bakelite) at
a density of 5.8 × 105
cells/cm2. Seeded cells were cultured in a
humidified 5% CO2 incubator at 37°C. After 1 d of culture, the medium was changed, and then the neurotrophic factors
and antibodies were added. Culture was continued for 6 d. Choline
acetyltransferase (ChAT) activity was assayed according to the method
described previously (Hatanaka and Tsukui, 1986).
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RESULTS |
Whole-cell patch-clamp recordings were performed from pyramidal
cell-like neurons in layer II/III of the visual cortex. To check
possible changes in recording conditions and membrane properties of
cells under observation, we continuously monitored series and input
resistances. If these values changed >20% of the initial control, the
recordings were stopped and the data were deleted from the analysis.
Eighty-four neurons that were recorded for longer than 40 min satisfied
these criteria. In the 61 neurons in which the initial control records
were obtained without any drug, single shocks applied to layer IV of
the cortex induced inward currents with the mean peak latencies and
amplitudes of 7.4 ± 2.0 (SD) msec and 115.1 ± 59.9 pA,
respectively, at the membrane potential of 70 mV (see specimen
records of Figs. 1, 3, and 7). These
currents were judged as monosynaptically elicited EPSCs on the basis of
the published criteria, such as very short and constant latency and
reversal potential near 0 mV (Yoshimura and Tsumoto, 1994). After test
shocks of layer IV at 0.1 Hz were confirmed to elicit EPSCs in the
stable condition for 10 min, LFS was given at 1 Hz for 10 or 15 min to
the same site in layer IV. In seven neurons, pair-pulse stimulation at
the interval of 50 msec was applied to layer IV at 0.1 Hz without LFS,
as will be described later.
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Figure 1.
Dependence of LTD induction on postsynaptic
membrane potential. A, An example of ineffectiveness for
LFS to induce LTD when the membrane potential of a postsynaptic neuron
was clamped at 70 mV. At the top are shown examples of
EPSCs recorded at the time point indicated by corresponding letters in
the bottom graph. Each record is obtained by
superimposition of six consecutive sweeps. The peak amplitude and the
initial slope of EPSCs are plotted against time in the
top and bottom graphs, respectively. The
value is expressed as the percentage of the mean of 60 responses before
LFS. The time when LFS was applied to layer IV is indicated by a
horizontal bar. B, An example of LTD
induced by LFS that was paired with depolarization of a postsynaptic
neuron to 30 mV. The peak amplitude and the initial slope of EPSCs
are plotted against time in the top two graphs. In the
bottom two graphs, the series resistance of the
electrode and the membrane resistance of the cell are plotted against
time. Other conventions are the same as in A.
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Dependence of the induction of LTD on
postsynaptic depolarization
Initially we found that LFS of layer IV did not induce LTD of
EPSCs in most of layer II/III neurons when the membrane potential was
kept at 70 mV during the LFS. An example of this finding is shown in
Figure 1A. In this case the duration of LFS was set to 15 min to exclude the possibility that the shorter duration of LFS
might make the induction of LTD infrequent. As shown in the top graph
of Figure 1A, the peak amplitude of EPSCs seemed to
be slightly depressed after the LFS with the clamped membrane potential
of 70 mV. However, they rapidly recovered to the original control
level within 5 min and thereafter remained at the control level until
20 min after cessation of the LFS. The peak amplitude of EPSCs might be
contaminated with inhibitory currents, so we also measured the initial
slope of EPSCs (Fig. 1A, bottom graph). The initial slope changed in parallel with the peak amplitude of EPSCs
after the LFS. Such parallelism between the peak amplitude and the
initial slope of EPSCs was seen in other cells also (Fig. 1B). In the present study, we used the initial slope
of EPSCs for evaluation of changes in excitatory synaptic response to
minimize the above-mentioned possibility of contamination of inhibitory currents. Mean values of the initial slope of EPSCs for nine cells were
plotted against time in Figure
2A. In seven of the
nine cells, LFS was applied to layer IV for 10 min, because this
duration of LFS, if paired with postsynaptic depolarization to 30 mV, consistently induced LTD, as will be described later. The mean value of
ratios of the EPSC slope 15-20 min after cessation of LFS to that
before the LFS was 96.0 ± 18.5% (SD) for the seven cells. This
value was not significantly different from that (96.6 ± 6.4%)
for the other two cells tested with LFS of the 15 min duration.
Therefore, these data were combined in Figure 2A and treated as a single group of data in the present study.
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Figure 2.
Time courses of the mean EPSC slope. For each
cell, the mean slope of six consecutive EPSCs was calculated as a
percentage of that of 30 control EPSCs before LFS. Vertical
bars indicate twice the SEM. In A, LFS*
indicates that its duration was 10 min for seven cells and 15 min for
the other two cells. The values after cessation of the LFS were
combined as described in Results. Thus, the
numbers in parentheses along the abscissa
indicate the time for the latter two cells. In all nine cells the
membrane potential was kept at 70 mV throughout recordings. In
B and C, LFS was paired with
depolarization of recorded cells to 30 and 50 mV, respectively. The
duration of LFS was 10 min, as indicated by horizontal
bars. Other conventions are the same as in A. In
D, recorded cells were depolarized to 30 mV without
layer IV stimulation, as indicated by the horizontal
bar. Other conventions are the same as in
A.
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We then attempted to determine conditions in which LTD of EPSCs of
patch-clamped neurons was induced reliably by LFS of layer IV. We found
that LTD was induced consistently when LFS was paired with
depolarization of recorded neurons to 30 mV. An example of this
finding is shown in Figure 1B. In this neuron the
mean peak amplitude and initial slope of control EPSCs before LFS was 99.0 ± 12.2 pA and 28.1 ± 10.9 nA/sec, respectively. After
LFS was combined with depolarization to 30 mV for 10 min, the
amplitude and slope of EPSCs decreased to ~65 and 60% of the
control, respectively, and remained at this level 20 min after
cessation of the LFS. This depression of EPSCs was not caused by
a deterioration of the recording and neuronal conditions, because the
series and membrane resistances were very stable (Fig.
1B, bottom two graphs). Mean EPSC slopes
for nine cells were plotted in Figure 2B. It is
obvious that LTD was induced by LFS that was paired with depolarization of postsynaptic neurons to 30 mV.
Then, we tested to what degree depolarization is necessary to induce
LTD. For this, LFS of layer IV was paired with depolarization of the
membrane potential to 50 mV in another nine cells. As shown in Figure
2C, this pairing procedure did not yield LTD of EPSCs. The
mean value of ratios of the EPSC slope 15-20 min after LFS to that
before LFS for the nine cells was 91.8 ± 15.9% (SD), which was
not significantly (p = 0.16; paired t
test) different from the control. In the present study, we did not
systematically change the membrane potential of recorded cells, because
we were not interested in the threshold for the postsynaptic
depolarization to induce LTD, but rather in the action of BDNF on LTD.
There is a possibility that LTD induced by pairing of LFS with the
depolarization of the recorded neurons to 30 mV might be attributable
to strong postsynaptic depolarization per se. To test this possibility, eight neurons were depolarized to 30 mV (duration, 100 msec) at 1 Hz
for 10 min without layer IV stimulation. As a whole, EPSCs were not
significantly depressed (Fig. 2D). The mean value of the EPSC slope 15-20 min after cessation of the depolarization procedure for the eight cells (96.3 ± 13.5%) was not
significantly different from the control.
Blockade of LTD by exogenous BDNF
As reported previously (Akaneya et al., 1997), BDNF at the
concentration of 20 ng/ml did not significantly change EPSCs evoked by
test stimulation of layer IV at 0.1 Hz. In the present study, however,
we found that BDNF at this concentration did block LTD of EPSCs even
when LFS was paired with depolarization of postsynaptic neurons to 30
mV. An example of this finding is shown in Figure 3A. Twenty minutes after
initiation of the BDNF application, LFS paired with the depolarization
of this neuron to 30 mV was applied to layer IV at 1 Hz for 10 min.
Such a pairing procedure turned out to be ineffective. After cessation
of the LFS, the amplitude and initial slope of EPSCs were not decreased
at all (Fig. 3A). Mean EPSC slopes for the eight cells
tested in this way were plotted in Figure
4A. It is evident that
LTD was not induced by LFS. The mean value of ratios of the EPSC slope
15-20 min after LFS to that before the LFS for the eight cells was
98.4 ± 19.4%. Without BDNF, LFS of the same parameters induced
significant LTD in all of the nine cells, as mentioned above (Fig.
2B). The mean ratio for the nine cells was 55.6 ± 17.4%. The difference between these two values was statistically
significant (p < 0.001; unpaired t
test).
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Figure 3.
Blockade of LTD by BDNF (A),
and effective (B) and ineffective
(C) antagonism by K252a applied through the
medium and K252b injected into a postsynaptic neuron, respectively. The
initial slope of EPSCs is plotted against time in the graphs. The value
is expressed as the percentage of the mean of 60 responses before LFS.
An open, horizontal bar indicates the period during
which BDNF was applied to the slice. In B, K252a (300 nM) was applied to a slice, as indicated by a
shaded, horizontal bar, simultaneously with BDNF. In
C, K252b (200 nM) was injected into a neuron
through a patch pipette. Other conventions are the same as in Figure
1A.
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Figure 4.
Time courses of the mean EPSC slope in the
conditions as indicated. Conventions are the same as in Figure 2. In
A, BDNF was applied to slices, as indicated by the
open, horizontal bar, and then LFS was paired with 30
mV depolarization of recorded neurons during the period indicated by
the filled horizontal bar. In B, BDNF and
K252a were applied to slices through the perfusion medium, as indicated
by horizontal bars. In C, K252b was
injected into recorded neurons through patch pipettes, and BDNF was
applied to slices through the medium, as indicated by the open,
horizontal bar.
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Next, we tested whether K252a could antagonize such a blocking action
of BDNF on the LTD induction. K252a is a membrane-permeable inhibitor
for Trk receptor tyrosine kinases without affecting other tyrosine
kinases at the concentration of 200-300 nM, and thus is an
effective blocking agent on biological actions of BDNF and other
neurotrophins (Knüssel and Hefti, 1992; Tapley et al., 1992). As
reported previously (Akaneya et al., 1996, 1997), an application of
K252a at this concentration did not significantly change synaptic
responses of layer II/III neurons evoked by test stimulation of layer
IV at 0.1 Hz. When K252a was coapplied with BDNF, LFS paired with the
depolarization of postsynaptic neurons to 30 mV induced LTD of EPSCs.
An example of this finding is shown in Figure 3B. In this
case, the initial slope of EPSCs 15-20 min after the paired LFS
decreased to 55.4 ± 17.2% of the control. This result indicates
that K252a antagonized the LTD-blocking action of BDNF. Mean EPSC slope
for the nine cells tested in this way shows that LFS of layer IV during
the coapplication of BDNF and K252a induced LTD of EPSCs (Fig.
4B), although the magnitude of LTD (73.5 ± 16.5%, 15-20 min after LFS) was slightly but significantly (p < 0.05; unpaired t test) smaller
than that induced by paired LFS alone. This might be attributable to an
imperfect action of K252a at 200-300 nM in the slice
preparations. Nevertheless, the value of 73.5 ± 16.5% was
significantly (p < 0.02; unpaired t test) smaller from that (98.4 ± 19.4%) of the eight cells
without K252a but with BDNF (Fig. 4A). In sum, these
results suggest that the blockade of LTD by BDNF is mediated at least
in part through an activation of Trk receptor tyrosine kinases.
Then, we examined the question of whether the site of the activation of
Trk receptor tyrosine kinases by BDNF is presynaptic or postsynaptic.
For this, K252b was injected into postsynaptic neurons through patch
pipettes. K252b is a membrane-impermeable inhibitor of Trk receptor
tyrosine kinases over a wide range of concentrations without being
cytotoxic (Knüssel and Hefti, 1992). To confirm that K252b
actually spread to the whole dendritic region of postsynaptic neurons,
a mixture of K252b and rhodamine was injected into four neurons through
whole-cell patch pipettes. The molecular weights of K252b and the dye
are similar (453.5 and 606.7, respectively), and thus they are expected
to spread almost equally. The fluorescent dye was observed to spread to distal parts of dendrites of layer II/III pyramidal neurons
approximately 20 min after the cell membrane had been ruptured (Fig.
5). It is to be noted that the stable
recording of EPSCs was usually obtained at least 10 min after the
formation of patch-clamp recording configuration, and thus LFS was
initiated at least 20 min after the rupture of the membrane. Therefore,
K252b is expected to spread to almost the whole dendritic region at a
concentration not very different from that in pipettes, when LFS was
applied to layer IV.
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Figure 5.
A fluorescent image of a pyramidal neuron into
which a mixture of K252b and rhodamine was injected through a patch
pipette, which is seen to be attached to the soma. This cell was
located in layer II/III of the cortex so that the right side of the
figure corresponds to layer I of the cortex. Scale bar, 20 µm.
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Figure 3C shows an example of the results obtained from the
experiments in which the possibility of postsynaptic action of K252b
was tested. About 10 min after having obtained the configuration of
whole-cell patch-clamp recording with a pipette containing K252b at 200 nM, EPSCs became stable and then remained almost constant.
Ten minutes later, BDNF at 20 ng/ml was applied to this cell
through the perfusion medium. EPSCs were not significantly changed by
BDNF (Fig. 3C, record b). Then, LFS paired with
depolarization of this cell to 30 mV was applied to layer IV, but
EPSCs were not depressed at all (Fig. 3C, record
c and graph). Mean EPSC slopes for the six cells
tested in this way were plotted in Figure 4C. The mean value
of ratios of the EPSC slope 15-20 min after LFS to that before the LFS
for this group of cells (95.5 ± 19.5%) was nearly equal to that
of the cells with BDNF alone (Fig. 4A), indicating
that the injection of K252b into postsynaptic neurons could not
antagonize the action of BDNF.
The ineffectiveness of the postsynaptic injection of K252b but the
effective blockade of the BDNF action by the bath application of K252a
suggests that the site of its action is presynaptic. To confirm this
suggestion, we observed EPSCs evoked by pair-pulse stimulation of layer
IV and measured the ratio of the initial slope of second EPSC to that
of first EPSC [pair-pulse ratio (PPR)], because PPR is thought to be
an indicator of a change in presynaptic processes of transmitter
release (Zucker, 1989). So, we stimulated layer IV with pair-pulse
shocks at the interval of 50 msec and measured PPRs before and after
the application of BDNF at 20 ng/ml in seven neurons. Consistent with
the previous report (Torii et al., 1997), five of the seven cells
showed pair-pulse depression, and the other two cells did not show
pair-pulse depression or potentiation. The mean PPR for the seven cells
was 0.83 ± 0.16 (SD). After the application of BDNF, EPSCs to
second stimuli were relatively enhanced in most of the cells, and
consequently the mean PPR of these seven cells was increased to
0.98 ± 0.22. The difference between these two values is
statistically significant (p < 0.01; paired
t test). This confirms the suggestion that the site of the
BDNF action is presynaptic.
Emergence of LTD during the inhibition of endogenous BDNF
As the next step of analysis, we attempted to determine whether
endogenous BDNF has a role in the blockade of LTD similar to that of
exogenous BDNF, as mentioned above. In other words, the ineffectiveness
of LFS without postsynaptic depolarization might be caused by the
LTD-blocking action of endogenous BDNF. To test this possibility, we
initially applied K252a to cortical slices, and LFS was given to layer
IV without postsynaptic depolarization. In seven of the nine cells
tested in this way, LFS effectively induced LTD even when the membrane
potential was clamped at 70 mV. The mean value of ratios of the EPSC
slope 15-20 min after LFS to that before LFS was 72.4 ± 9.1%
for the nine cells.
The action of K252a is not strictly selective for TrkB receptor
tyrosine kinases. To block the action of endogenous BDNF more selectively, therefore, we used the polyclonal antibody against BDNF.
This antibody reacted with BDNF but not with NGF and neurotrophin-3 (NT-3) (Fig. 6A). Then,
we tested whether the antibody could block biological activities of
BDNF selectively and if so at what concentration. For this test,
dissociated primary cultures of basal forebrain neurons obtained from
embryonic rats were prepared, and ChAT activity was assayed according
to the method as described previously (Hatanaka and Tsukui, 1986).
Results obtained from this assay are shown in Figure
6B. The antibody at the concentration of 1 µg/ml
clearly antagonized the action of BDNF, whereas it did not block that of NGF. This indicates that the antibody at 1 µg/ml could selectively block the biological activity of BDNF. The antibody might not easily
penetrate into slices, even if the slices were incubated with the
antibody for ~1 hr. Initially, therefore, we incubated seven slices
with the antibody at the concentration of 5 µg/ml and found a clear
antagonizing effect against BDNF. In three other slices, we used the
antibody at 1 µg/ml, which again showed the same degree of the
antagonizing effect. So, the data obtained with the two concentrations
of the antibody were combined in the present analysis. An example of
the results obtained with the antibody at 1 µg/ml is shown in Figure
7A. As shown in specimen records, test stimulation of layer IV elicited EPSCs with the mean peak
latency and amplitude of 6.1 ± 0.4 msec and 147.1 ± 12.4 pA, respectively. These values were within those of control EPSCs
without the antibody. For the 10 cells incubated with the antibody, the
mean peak latency and amplitude of control EPSCs were 8.4 ± 1.8 msec and 110.1 ± 42.0 pA, respectively, which were not
significantly different from those of the other neurons (7.5 ± 1.9 msec and 116.1 ± 57.2 pA, respectively). Thus, the incubation of slices with the anti-BDNF antibody did not affect control EPSCs of
layer II/III neurons evoked by layer IV stimulation at 0.1 Hz. In the
cell shown in Figure 7A, LFS of layer IV induced a clear LTD
even when the cell was clamped at 70 mV. The mean value of the
initial slope of EPSCs 15-20 min after LFS was 70.0 ± 9.8% of
the control. This LTD was not caused by a deterioration of the cell
condition, because the membrane resistance was fairly constant (Fig.
7A, bottom histogram). For the 10 cells tested in
this way, mean EPSC slopes were plotted in Figure 7B. The
mean value of ratios of the EPSC slope 15-20 min after LFS to that before the LFS (69.1 ± 21.8%) was significantly
(p < 0.01; unpaired t test) smaller
than that (96.1 ± 16.2%) of the cells clamped at 70 mV without
any drug or antibody, as shown in Figure 2A.
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Figure 6.
Specificity of the anti-BDNF antibody.
A, Western blot. NGF (purified mouse
submandibular -NGF, 2.6 ng), BDNF (recombinant human
BDNF, 2.5 ng), and NT-3 (recombinant human NT-3, 2.5 ng)
were loaded in respective lanes. The blot was stained with the
anti-BDNF antibody. An arrow indicates a band
corresponding to a subunit of BDNF with molecular mass of 14 kDa.
B, Assay of activity of the anti-BDNF antibody. Action
of the antibody on ChAT activity enhanced by BDNF or NGF was examined
in the conditions as indicated at the bottom. Each
column with short bars indicates the mean ± SD of
the mean for the four determinations.
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Figure 7.
Emergence of LTD during the inhibition of activity
of endogenous BDNF. A, An example of LTD induced by LFS
without postsynaptic depolarization in a slice that was perfused with
the anti-BDNF antibody at the concentration of 1 µg/ml. Other
conventions are the same as in Figure 1A. In the
bottom graph, the membrane resistance of this neuron is
plotted against time. B, Time course of the mean EPSC
slope for 10 neurons. Slices containing these neurons had been
incubated with the anti-BDNF antibody. Other conventions are the same
as in Figure 2.
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DISCUSSION |
In the present study we found that LFS of layer IV induces LTD of
EPSCs of layer II/III neurons in the visual cortex of young rats if
each shock of the LFS is paired with depolarization of the neurons to
30 mV, but such a paired LFS becomes ineffective during the
application of BDNF. This indicates that exogenously applied BDNF
prevents paired LFS from inducing LTD of synaptic transmission.
Considering the existence of endogenous BDNF in the cerebral cortex
(Wetmore et al., 1991; Dugich-Djordjevic et al., 1995; Nawa et al.,
1995; Katoh-Semba et al., 1997; Yan et al., 1997a), it is also possible
to state that endogenous BDNF alone cannot block the induction of LTD
by paired LFS. The present results also demonstrate that the inhibition
of activity of endogenous BDNF by the anti-BDNF antibody or K252a makes
the otherwise ineffective LFS effective for the induction of LTD in
most of the neurons that were voltage-clamped at 70 mV. This suggests
that endogenous BDNF may prevent repetitive, low-frequency inputs to
cortical synapses from inducing LTD if postsynaptic neurons are not
depolarized or only weakly depolarized. In the physiological condition,
however, cortical neurons are not voltage-clamped so that repetitive
inputs would generate a strong postsynaptic depolarization. It is
known, however, that repetitive synaptic inputs at low frequencies such as 1 Hz do not always generate strong depolarizations or action potentials of neurons in hippocampus (Mulkey and Malenka, 1992) and
visual cortex (Dudek and Friedlander, 1996), probably because of no
summation of excitatory responses and/or a concomitant activation of
inhibitory circuits. Thus, it seems possible that repetitive, low-frequency inputs to cortical synapses could not induce LTD in the
presence of endogenous BDNF. In other words, endogenous BDNF is assumed
to prevent such inputs from inducing LTD in the physiological condition.
In the developing visual cortex, it is suggested that cortical synapses
are bombarded by repetitive inputs originated from retinal spontaneous
activity at various frequencies, including the range of LFS (Shatz,
1990). Furthermore, immature synapses in the cortex are known to be
easily suppressed by such repetitive inputs (Dudek and Bear, 1993;
Dudek and Friedlander, 1996). Taking these and the above-mentioned
considerations altogether, it seems reasonable to suggest that
endogenous BDNF may prevent immature cortical synapses from being
depressed by such spontaneous inputs during postnatal development.
The site in which BDNF exerts its action: tentative models
As mentioned above, a substantial depolarization of cortical
neurons in conjunction with repetitive synaptic inputs at 1 Hz for
10-15 min is necessary for the induction of LTD. This result indicates
that processes for the induction of LTD may take place at postsynaptic
sites. On the other hand, the previous study using the same type of
preparations as the present ones suggested that LTD of layer II/III
neurons in the visual cortex is expressed at presynaptic sites (Torii
et al., 1997). Thus, it seems reasonable to conclude that the locus for
the induction of LTD is postsynaptic, but that the expression is
presynaptic in visual cortex, as reported in the CA1 area of the
hippocampus (Bolshakov and Siegelbaum, 1994; Stevens and Wang, 1994).
This suggests that there is a retrograde messenger that might act as an
LTD expression factor in the visual cortex (Fig.
8A).
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Figure 8.
Schematic diagrams showing the two models for the
blocking action of BDNF on LTD. In A, BDNF is
hypothesized to be derived from presynaptic sites and to serve as an
inhibitor for an LTD expression factor that would be released from
postsynaptic sites. In this model, LFS is supposed to induce a mild
level of depolarization and a consequent rise of
Ca2+ in postsynaptic sites through activation of
glutamate receptors (Glu-R) and voltage-dependent
Ca2+ channels (VDCC). This rise of
Ca2+ would activate an unknown process, which in
turn would release or produce the LTD expression factor. This factor
would decrease transmitter release from presynaptic terminals for a
long time. The activation of TrkB by BDNF would then suppress the
action of this factor in presynaptic terminals. In B,
BDNF itself is hypothesized to operate as an LTD-blocking or a synaptic
transmission-maintaining factor. The LFS-induced rise in postsynaptic
Ca2+ would activate an unknown factor, possibly
protein phosphatases, which would suppress the release or production of
BDNF at postsynaptic sites. This would in turn lead to a shortage of
BDNF at presynaptic terminals. Thus, LFS without support of BDNF would
lead to a decrease in transmitter release from presynaptic terminals
for a long time.
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|
Then, an obvious question is this: in which site BDNF does exert its
action? Previous studies with immunohistochemistry reported that
high-affinity receptors for BDNF, TrkB receptors, exist both at
presynaptic axons and postsynaptic dendrites and soma in the cortex
(Cabelli et al., 1996; Fryer et al., 1996; Yan et al., 1997b). The
present results that the injection of K252b into postsynaptic neurons
was not effective to block the action of BDNF, whereas the perfusion of
K252a to the whole slice was effectivesuggest that BDNF exerts its
action on the expression mechanism in presynaptic sites. This
suggestion was further confirmed by the result that the PPR of EPSCs
was changed by the application of BDNF in most of the cases in which
pair-pulse stimulation was given to layer IV. Previous studies also
suggest that BDNF acts on presynaptic sites to increase the release of
transmitters (Lohof et al., 1993; Lemann et al., 1994; Kang and
Schuman, 1995; Stoop and Poo, 1996; Carmignoto et al., 1997; Gottschalk
et al., 1998; Lemann and Heumann, 1998). Then, the next question is
this: from which site is BDNF derived? Recently it has been suggested
that BDNF is transported anterogradely and localized around vesicles in
presynaptic terminals (von Bartheld et al., 1996; Conner et al., 1997;
Fawcett et al., 1997). Thus, it is possible to assume that BDNF
released from axon terminals activates TrkB receptors at the terminals,
which in turn inhibits the action of an LTD expression factor (Fig. 8A). However, this possibility seems inconsistent
with the present result that LTD was induced by LFS without
postsynaptic depolarization during the application of the anti-BDNF
antibody. In this situation the postsynaptic process was not activated,
so that the LTD expression factor would not be produced or released.
Nevertheless the inactivation of BDNF by the antibody resulted in the
induction of LTD by LFS.
Thus, we are led to an alternative hypothesis (Fig.
8B). In this hypothesis BDNF itself is supposed to
act as a retrograde messenger, as suggested previously (Thoenen, 1995;
Bonhoeffer, 1996; Katz and Shatz, 1996). A novel point of this
hypothesis is that the basal level of BDNF would be released as a
transmission-maintaining factor from postsynaptic neurons with the
membrane potential at or near the resting level, but its release would
be decreased during the moderate level of postsynaptic depolarization
induced by LFS. A very strong depolarization that is induced by
high-frequency inputs would rather increase the release of BDNF, as
suggested in hippocampal neurons that were depolarized very strongly
with high K+ solution (Blöchl and Thoenen,
1995; Goodman et al., 1996). The increased BDNF at presynaptic sites
then would play a role in the maintenance of LTP, as suggested
previously (Kang and Schuman, 1995; Akaneya et al., 1997). On the other
hand, the moderate level of depolarization induced by LFS would
activate a factor that suppresses the release or production of BDNF.
Thus, the decrease in release of BDNF from postsynaptic sites and the
consequent shortage of BDNF at presynaptic sites may lead to LTD. In
other words, LFS would depress synaptic transmission for a long time if
a certain amount of BDNF is not available to presynaptic sites. This
hypothesis seems consistent with the results obtained in the present
study. For example, the inhibition of activity of BDNF by the antibody
would result in LTD without postsynaptic depolarization. The factor
that reduces the release or production of BDNF in response to the
moderate level of postsynaptic depolarization might be
Ca2+/calmodulin-dependent protein phosphatase,
whereas the factor with the opposite action might be
Ca2+/calmodulin-dependent protein kinases, as
suggested previously (Tsumoto, 1992; Bear and Malenka, 1994; Singer,
1995). However, little is known about the intracellular processes that
control the release or production of BDNF, and thus more experimental data are necessary for the establishment of this hypothesis.
| |
FOOTNOTES |
Received Oct. 1, 1998; revised Dec. 21, 1998; accepted Dec. 29, 1998.
This study is supported by a Grant-in-Aid for Scientific Research
(07279102) from the Ministry of Education, Science, Sports and Culture
of Japan. We express many thanks to Sumitomo Pharmaceutical Co., Ltd.
and Kyowa Hakko Kogyo Co., Ltd. for kind gifts of recombinant human
BDNF and K252a, respectively. We also thank Dr. Yasuhiro Abiru for
helpful advice to performing the experiments.
Correspondence should be addressed Dr. Tadaharu Tsumoto, Department of
Neurophysiology, Biomedical Research Center, Osaka University Medical
School, 2-2 Yamadaoka, Suita City 565-0871 Japan.
| |
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T. Pizzorusso, G. M. Ratto, E. Putignano, and L. Maffei
Brain-Derived Neurotrophic Factor Causes cAMP Response Element-Binding Protein Phosphorylation in Absence of Calcium Increases in Slices and Cultured Neurons from Rat Visual Cortex
J. Neurosci.,
April 15, 2000;
20(8):
2809 - 2816.
[Abstract]
[Full Text]
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E. Kumura, F. Kimura, N. Taniguchi, and T. Tsumoto
Brain-derived neurotrophic factor blocks long-term depression in solitary neurones cultured from rat visual cortex
J. Physiol.,
April 1, 2000;
524(1):
195 - 204.
[Abstract]
[Full Text]
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R. A. Crozier, I. B. Black, and M. R. Plummer
Blockade of NR2B-Containing NMDA Receptors Prevents BDNF Enhancement of Glutamatergic Transmission in Hippocampal Neurons
Learn. Mem.,
May 1, 1999;
6(3):
257 - 266.
[Abstract]
[Full Text]
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Y. Hata, M. Ohshima, S. Ichisaka, M. Wakita, M. Fukuda, and T. Tsumoto
Brain-Derived Neurotrophic Factor Expands Ocular Dominance Columns in Visual Cortex in Monocularly Deprived and Nondeprived Kittens But Does Not in Adult Cats
J. Neurosci.,
February 1, 2000;
20(3):
RC57 - RC57.
[Abstract]
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Top
Abstract
Introduction
