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Volume 17, Number 17,
Issue of September 1, 1997
pp. 6707-6716
Copyright ©1997 Society for Neuroscience
Brain-Derived Neurotrophic Factor Enhances Long-Term Potentiation
in Rat Visual Cortex
Yukio Akaneya1,
Tadaharu Tsumoto1,
Shuichiro Kinoshita1, and
Hiroshi Hatanaka2
1 Department of Neurophysiology, Biomedical Research
Center, Osaka University Medical School, Suita City, 565 Japan, and
2 Division of Protein Biosynthesis, Institute for Protein
Research, Osaka University, Suita City, 565 Japan
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3),
members of the nerve growth factor (NGF) gene family, have been
suggested to play a role in experience-dependent modification of neural
networks in the developing nervous system. In this study we addressed
the question of whether these neurotrophins are involved in long-term
potentiation (LTP) in developing visual cortex. We recorded layer
II/III field potentials and whole-cell currents evoked by test
stimulation of layer IV at 0.1 Hz in visual cortical slices prepared
from young rats (postnatal day 15-25) and observed effects of BDNF,
NT-3, and NGF on these responses. Then we analyzed the effects of these
neurotrophins on LTP induced by tetanic ( -burst type) stimulation of
layer IV. We found that BDNF at 200 ng/ml potentiated field potentials
and EPSCs in most cases and that this potentiation lasted after
cessation of the BDNF application. At the concentration of 20 ng/ml,
BDNF did not show such an effect, but it enhanced the magnitude of
expressed LTP. On the other hand, NT-3 and NGF had none of these
effects. Immunohistochemical staining of slices with antibody against
BDNF showed that exogenous BDNF penetrated into the whole slice within
~5 min of its application. The actions of BDNF were blocked by
preincubation of slices with TrkB-IgG fusion protein, a BDNF scavenger,
or coapplication of K252a, an inhibitor for receptor tyrosine kinases.
TrkB-IgG or K252a itself completely blocked LTP, suggesting that
endogenous BDNF or another TrkB ligand plays a role in LTP in the
developing visual cortex.
Key words:
brain-derived neurotrophic factor;
long-term
potentiation;
nerve growth factor;
neurotrophin-3;
visual cortex;
synaptic plasticity
INTRODUCTION
Neurotrophins of the nerve growth
factor (NGF) family have been considered to play roles in the
differentiation, neurite outgrowth, and survival of developing neurons
and maintenance of a certain group of matured neurons (Levi-Montalcini,
1987 ; Barde, 1989; Davies, 1994). In addition to these well known
functions, accumulating evidence from recent studies suggests that the
neurotrophins are involved in more rapid changes in the CNS and
peripheral nervous system (Ip et al., 1993; Lohof et al., 1993; Kim et
al., 1994; Le mann et al., 1994; Kang and Schuman, 1995; Levine et
al., 1995; Wang et al., 1995; Stoop and Poo, 1996; Carmignoto et al.,
1997; for reviews, see Bonhoeffer, 1996; Lewin and Barde, 1996). In particular, brain-derived neurotrophic factor (BDNF) is suggested to
play a role in a form of synaptic plasticity, long-term potentiation (LTP), in the hippocampus (Castrén et al., 1992a; Patterson et al., 1992; Kang and Schuman, 1995; Figurov et al., 1996). Also, LTP in
the hippocampus is reported to be impaired in BDNF knockout mice (Korte
et al., 1995; Patterson et al., 1996)
In the developing visual cortex, it has been reported that the
experience-dependent plasticity of structure and function of neural
circuits is influenced by the neurotrophins, although the involvement
of NGF is a matter of controversy (Maffei et al., 1992; Carmignoto et
al., 1993; Cabelli et al., 1995; McAllister et al., 1995, 1996; Riddle
et al., 1995; Galuske et al., 1996; Hata et al., 1996). In addition,
the expression of BDNF mRNA in the rat visual cortex was shown to
decrease by visual deprivation (Castrén et al., 1992b; Bozzi et
al., 1995; Schoups et al., 1995). In this area of the cortex LTP has
been proposed as a synaptic basis for experience-dependent changes in
structure and function of neural circuits (for reviews, see Tsumoto,
1992; Singer, 1995). Thus, a question arises about whether the
neurotrophins are involved in LTP in the developing visual cortex. In
the present study, therefore, we tested whether BDNF, NGF, and another
neurotrophin, neurotrophin-3 (NT-3), have any effect on low-frequency
synaptic transmission and LTP in layer II/III of visual cortical slices of young rats.
Part of the data in this study has been published previously in
abstract form (Akaneya et al., 1996).
MATERIALS AND METHODS
Slice preparation. Sprague Dawley rats, aged from 15 to 25 postnatal days, were anesthetized deeply with ketamine (30 mg/kg, i.p.) (Sankyo, Tokyo, Japan) and then killed by cervical dislocation. Coronal slices of visual cortex (250-400 µm thickness) were cut using a rotor slicer (DTY7000, Dosaka, Kyoto, Japan). Procedures for
maintaining the slices were essentially the same as those described
previously (Kimura et al., 1989). In short, slices were submerged in a
stream of the perfusion medium at the rate of 200 ml/hr. The medium was
aerated with 95% O2/5% CO2. The
composition of incubation and perfusion medium of the slices was as
follows (in mM): 124 NaCl, 5 KCl, 1.2 KH2PO4, 1.3 MgSO4,
2.4 CaCl2, 26 NaHCO3, and 10 glucose. All of the recordings were performed at 30-31°C, unless
noted otherwise.
Stimulation of afferents and recording of field potentials or
synaptic currents. A bipolar stimulating electrode was placed in
layer IV of the cortex. To record field potentials evoked by test
stimulation of layer IV, glass micropipettes filled with 0.5 M sodium acetate containing 2% pontamine sky blue
(resistance <10 M ) were inserted into layer II/III of the cortex.
Procedures for recording field potentials were conventional, as
described previously (Kimura et al., 1989). In part of the experiments, EPSCs 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).
Whole-cell patch pipettes (resistance 4-8 M) were filled with a
solution containing (in mM): 130 potassium gluconate, 10 KCl, 10 HEPES, 3 MgATP, and 0.5 Na2GTP, and adjusted to pH
7.2 by KOH. The osmolarity of the solution was 280-285 mOsm. Visually
identified neurons were voltage-clamped at  70 mV with a patch-clamp
amplifier (Axopatch 200A or 200B, Axon Instruments). Membrane
potentials were corrected for the liquid junctional potentials. The
fast transient capacitive currents for recording electrodes were
canceled, and the series resistance was compensated. The series
resistance was <20 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 or 2 kHz. These data were analyzed mainly with pClamp
software (Axon Instruments).
Test pulses of 0.1 msec width were delivered at 0.1 Hz, and the
stimulus intensity was adjusted usually to 1.5 times the threshold to
elicit the postsynaptic component of field responses. In the experiments in which EPSCs were recorded through patch pipettes, the
stimulus intensity was 1.2-1.5 times the threshold for EPSCs. The
intensity of test shocks was usually 2.5-4.0 V in field potential recordings and 1.0-2.0 V in whole-cell recordings.
Tests with the neurotrophins and blockers. After having
confirmed that test shocks given to layer IV at 0.1 Hz induced constant responses for 10-20 min, human recombinant BDNF (Regeneron
Pharmaceutical Co., Tarrytown, NY), human recombinant NGF (Boehringer
Mannheim, Mannheim, Germany), human recombinant NT-3 (Promega, Madison, WI), or K252a (Kyowa Hakko Co., Tokyo, Japan) was applied to slices through the perfusion medium. In the experiments in which TrkB-IgG fusion protein (Genentech, San Francisco, CA) was tested, slices were
preincubated in the medium containing this protein (1 µg/ml) for 2-4
hr. The neurotrophins were prepared at the concentration of 500 mg/ml
containing 0.1% bovine serum albumin in undiluted Ca2+-, Mg2+-free PBS. They were
diluted to 20, 100, or 200 ng/ml with the perfusion medium just before
recordings. For application of K252a, this drug was prepared to be the
final concentration of 200 nM with dimethyl sulfoxide as
vehicle, of which the final concentration was 0.01% (v/v). Inactivated
BDNF was obtained by heating BDNF at 100°C for 5 min. 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 with silicone 2-3 d before recording.
To assess effects of BDNF, NT-3, NGF, and K252a, control responses to
single shocks given to layer IV were recorded for 10-20 min, and then
the neurotrophins or K252a were applied to slices through the medium
for 20 or 30 min. Responses were further observed for 30 min after
cessation of the application. To evaluate the effects quantitatively,
the means of the peak-to-peak amplitude and rising slope of the
postsynaptic component of field responses or those of the peak
amplitude and falling slope of EPSCs for 10 min before the application
were taken as control value. The slope was calculated using the value
for 10-90% of the rising or falling phase of the responses. When an
action of K252a on neurotrophin-induced effects was assessed, an
application of K252a was started at least 10 min before the application
of neurotrophins and continued until the end of recordings. In the
tests with TrkB-IgG, it had been applied to slices before recordings.
In these experiments, the mean value of the postsynaptic component of
responses for 10 min before the neurotrophin application was taken as
control. The statistical estimation for differences was performed with the Student's t test or the one-way ANOVA followed by the
Fisher's protected least significant difference multiple comparison
post hoc analysis.
To determine the effects of the neurotrophins, TrkB-IgG, or K252a on
LTP, tetanic stimulation was applied to layer IV. In the present study,
we used the following type of tetanic stimulation: a brief,
high-frequency pulse train (4 pulses at 100 Hz) given at the -rhythm
(5 Hz) for 2 sec and repeated five times at 10 sec intervals (-burst
tetanus). The width of each pulse was 0.2 msec, and its voltage was the
same as that of test stimulation. In the experiments in which the
neurotrophins or K252a were tested, control responses to single shocks
given to layer IV were recorded for at least 10 min, and then these
substances were applied to slices through the medium. In this
condition, responses to test stimulation were observed for 5 min, and
then tetanic stimulation was given to layer IV for 52 sec at the
-rhythm. After cessation of the tetanus, the neurotrophins or K252a
continued to be applied for another 20 or 30 min.
Immunohistochemical staining. Slices obtained 5 and 30 min
after starting and also after stopping the application of BDNF at the
concentration of 20 and 200 ng/ml and control slices before its
application were fixed in 4% paraformaldehyde (Sigma, St. Louis, MO)
for 1 hr, followed by overnight treatment with 30% sucrose in PBS.
Then slices were frozen and sectioned at 40 µm obliquely to the pial
surface for the deeper core of the slice to be exposed simultaneously
with the superficial rims on the same plane of the section. Sectioned
slices were washed with PBS, intermitted by washing with 50% ethanol.
These sections were incubated with 20% normal horse serum (Vector
Laboratories, Burlingame, CA) in PBS at least for 3 hr. Subsequently,
the sections were incubated with chicken polyclonal antibody against
human BDNF (Promega) at a dilution of 1:5000 in PBS containing 5%
(v/v) goat serum (Funakoshi, Tokyo, Japan), 0.3% Triton-X (Sigma), and
0.05% NaN3 for 3-4 d at 4°C. The sections were
incubated with 0.7 µg/ml biotinylated anti-chicken IgG (Vector) for
90 min, followed by further treatment with avidin-biotin complex
(Vector) for 60 min at room temperature. Positive reaction products
were visualized with 0.02% (w/v) 3,3 -diaminobenzidine 4-HCl (Sigma)
dissolved in 0.05 M Tris-buffered saline containing 0.01%
(v/v) H2O2. Specificity of the anti-BDNF
antibody was tested by substitution of normal chicken serum for the
antibody or by omission of the antibody from the immunohistochemical
procedures.
RESULTS
Potentiation of synaptic currents by BDNF
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 by >20%, the recordings were
stopped and the data were deleted. Of the 21 cells observed for longer
than 50 min, eight neurons satisfied these criteria during such
long-lasting recordings. In these eight neurons, single shocks applied
to layer IV of the cortex induced inward currents lasting for 53.6 ± 7.6 msec (SEM), with mean peak latencies of 7.5 ± 0.6 msec and
decay time constants of 11.0 ± 2.6 msec at the membrane potential
of 70 mV. These currents were judged as monosynaptically evoked 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 were confirmed to elicit EPSCs in the
stable condition for 10 min, BDNF was applied to slices. As will be
described later, tests with field potential recordings showed that BDNF
at the concentration of 20 ng/ml did not significantly change responses evoked by layer IV stimulation at 0.1 Hz. Therefore, we applied BDNF at
the concentration of 200 ng/ml and found that it clearly enhanced EPSCs
in most of the cells. Figure 1 shows an
example of EPSCs and a time course of their amplitude and slope and of series resistance of the recording system before, during, and after the
application of BDNF. The peak amplitude of EPSCs might be contaminated
by inhibitory currents, so we also measured the initial slope of EPSCs.
A few minutes after the BDNF application was initiated, the amplitude
and slope of EPSCs began to increase gradually and attained the plateau
value ~20 min later. Moreover, the enhancement of EPSCs lasted
without decline for at least 30 min after cessation of the BDNF
application. The fairly constant series resistance indicates that the
recording condition was very stable (Fig. 1D). As
shown in Figure 1B,C, the amplitude of EPSCs changed
in the same way as the slope did, although the magnitude of change in
the former value was slightly smaller than that in the latter. Such
parallelism of the two measures was also seen in other cells.
Subsequently, therefore, we measured the peak amplitude of EPSCs to
evaluate the effect of BDNF. In six of the eight cells, EPSCs were
significantly (paired t test; p < 0.05) potentiated, as shown in Figure 4 (filled
circles).
Fig. 1.
Potentiation of EPSCs by BDNF. A,
Examples of EPSCs recorded from a pyramidal cell-like neuron in layer
II/III of the cortex before (a), during
(b), and after (c) the
application of BDNF. Test stimulation was given to layer IV at 0.1 Hz.
Membrane potential was clamped at 70 mV. The time when each record
was obtained is shown by corresponding letters in B:
superimposition of five sweeps. B, C,
Plots of the peak amplitude and falling slope of EPSCs against time,
respectively. The value is expressed as the percentage of the mean of
60 responses before the application of BDNF. D, Plots of
the series resistance against time. The time when BDNF was applied to
the slice is indicated by a horizontal bar.
[View Larger Version of this Image (27K GIF file)]
Fig. 4.
Changes in response amplitude during neurotrophin
application. The ordinate represents the ratio of the mean amplitude of field responses (open circles) calculated from 30 responses for 25-30 min or that of EPSCs (filled
circles) from 30 responses for 15-20 min after starting the
neurotrophin application to that of 60 responses just before the
application. Short horizontal bars and vertical
bars represent means and twice the SEM for the same group of
slices or cells, respectively. The number of slices or cells used for
each test is shown at the top of each column.
[View Larger Version of this Image (15K GIF file)]
The stable recording of whole-cell synaptic currents for a long time is
a time-consuming task that often wastes neurotrophins and their
blockers because of interruption of recordings halfway. This is
particularly problematic in the present study, in which we attempted to
test the three kinds of neurotrophins and the two types of functional
blockers. As reported previously and confirmed in the present study,
the postsynaptic component of layer II/III field potentials corresponds
to EPSPs or EPSCs recorded from layer II/III neurons (Kimura et al.,
1989; Kirkwood et al., 1993). In fact, we observed that the
postsynaptic component of field potentials changed in parallel with
EPSCs after the application of BDNF (Figs. 1,
2). In the subsequent experiments,
therefore, we measured the postsynaptic component of layer II/III field
potentials evoked by test stimulation of layer IV to assess actions of
those substances on synaptic transmission in layer II/III of the visual
cortex.
Fig. 2.
Potentiation of field responses by BDNF.
A, Examples of field responses of layer II/III to test
stimulation of layer IV, recorded at the time points indicated by
corresponding letters in B. Arrows indicate the postsynaptic component of responses. Initial upward (negative) peaks are potentials evoked antidromically by layer IV
stimulation. B, C, Plots of the amplitude
and rising slope of the postsynaptic component of field potentials
against time, respectively. BDNF at 200 ng/ml was applied to the slice
during the period indicated by horizontal bar. In
B, the amplitude of the postsynaptic component from the
preceding positive (downward) to negative peak was measured and
expressed as the percentage of the mean of 60 responses before the
application of BDNF. In C, the slope of the rising phase
(from 10 to 90% point) of the postsynaptic component was measured and
expressed in the same way as in B.
[View Larger Version of this Image (40K GIF file)]
Potentiation of field potentials by BDNF
From layer II/III of the cortex, field responses consisting of two
components were elicited by single shocks applied to layer IV of the
cortex (Figs. 2A, 6A), as reported
previously (Kirkwood et al., 1993; Haruta et al., 1994). The initial
and second components of responses were judged as antidromically and
postsynaptically induced, because they were resistant and sensitive to
the Ca2+-free solution, respectively.
Fig. 6.
Enhancement of LTP by BDNF. A,
Examples of layer II/III field responses to test stimulation of layer
IV, recorded at the time points indicated by corresponding letters in
B. Other conventions are the same as in Figure
2A. B, Time course of the
amplitude of postsynaptic component of responses to test stimulation of layer IV. Tetanic stimulation was given to layer IV at the time 0, indicated by arrow. The amplitude of responses is
calculated as the percentage of the mean of 60 responses before the
application of BDNF.
[View Larger Version of this Image (28K GIF file)]
After test shocks of layer IV were confirmed to elicit field responses
with almost constant amplitude for 10-20 min, BDNF, NT-3, or NGF was
applied to slices at a given concentration. Initially we applied BDNF
at the concentration of 20 ng/ml for 20 or 30 min. The application of
BDNF at this concentration did not significantly change field responses
evoked by layer IV stimulation at 0.1 Hz, so we increased its
concentration to 200 ng/ml and found that BDNF clearly enhanced field
responses in most of the slices tested. Figure 2 shows an example of
responses and a time course of the amplitude and slope of the
postsynaptic component of responses before, during, and after the
application of BDNF. Approximately 5 min after the BDNF application was
initiated, the postsynaptic component began to increase gradually and
attained the plateau value ~10 min later. Moreover, the enhancement
of the responses lasted without decline for at least 30 min after
cessation of the BDNF application. As shown here, the peak-to-peak
amplitude of the postsynaptic component of field potentials changed in
parallel with the slope of its rising phase. Such a parallel change
between the two measures was seen in other slices. In the present
study, therefore, we measured the peak-to-peak amplitude of the
postsynaptic component. The mean amplitudes for the 15 slices after the
application time of 8 min were significantly (paired t test;
p < 0.05) larger than those before its application
(Fig. 3A). In six slices in which the control recording period preceding the BDNF application was
20 min, the amplitude of the responses during the last 10 min was not
different from that during the initial 10 min. Therefore, the
preapplication control period was set at 10 min in most cases. The
enhancing effect of BDNF was not observed at the concentration of 20 ng/ml, as mentioned above (Fig. 3D). The application of BDNF
at the concentration of 100 ng/ml showed a weak, but significant (paired t test; p < 0.05) augmentation of
responses after the application time of 16 min (Fig. 3C). In
the left three columns of Figure 4, the
ratio of the field potential amplitude 25-30 min after starting the
BDNF application to that before the application is plotted for each
slice. The difference in the mean value between 20 and 200 ng/ml was
statistically significant (unpaired t test; p < 0.0005). These results indicate that BDNF enhances
the efficacy of synaptic transmission in layer II/III of the visual
cortex in a dose-dependent manner. Unlike BDNF, however, NT-3 and NGF at the concentration of 200 ng/ml had no effect on layer II/III responses to test stimulation of layer IV in the visual cortex (Fig. 4,
second from right and far right columns).
Fig. 3.
Time courses of the mean amplitude of field
responses. For each slice, the mean of six consecutive responses was
calculated as a percentage of that of 60 control responses before the
application of BDNF. Vertical bars indicate twice the
SEM. Circles without vertical bars indicate that the
value of SEM was smaller than that of the radius. A-D,
BDNF was applied to slices as indicated by horizontal
bars. In A, the asterisk
indicates that the number of slices during the marked period was six;
otherwise the number of slices was 15. In B, slices were
preincubated with TrkB-IgG. The number of slices used for each test is
shown at the top of each graph.
[View Larger Version of this Image (25K GIF file)]
We then examined the question of whether these actions of BDNF are
mediated through tyrosine kinase receptors, because biological actions
of BDNF on neurons are known to be mediated via TrkB receptors (for
reviews, see Bothwell, 1995; Thoenen, 1995). To test this question we
used TrkB-IgG fusion protein, which competes with TrkB receptors for
binding BDNF (Shelton et al., 1995), and K252a, which inhibits tyrosine
kinase activity of Trk receptors (Kase et al., 1986; Koizumi et al.,
1988; for review, see Knüsel and Hefti, 1992). We initially
tested whether TrkB-IgG or K252a itself has any effect on synaptic
transmission at 0.1 Hz in layer II/III of the cortex. The preincubation
with TrkB-IgG did not affect field potentials evoked by test
stimulation of layer IV at 0.1 Hz. The intensity of test shocks was set
in the same range as in the recordings without TrkB-IgG. The mean
amplitude of the postsynaptic component of field responses for the 41 slices that had been incubated with this protein was 0.70 ± 0.03 mV (SEM). This value was not significantly different from that
(0.77 ± 0.02 mV) for the 149 slices without TrkB-IgG. Also, the
application of K252a at the concentration of 200 nM did not
significantly change field responses in any of the seven slices tested.
The peak-to-peak amplitude of the postsynaptic component 30 min after starting its application was 98.2 ± 2.5% (SEM) of the control. We then tested whether TrkB-IgG or K252a could block the potentiating effect of BDNF. In slices that had been preincubated with TrkB-IgG, BDNF at 200 ng/ml did not induce significant change in field potentials (Fig. 3B; also see Fig. 4, fifth column from
left). In the experiments in which K252a was tested, it was
coapplied with BDNF (200 ng/ml) and was found to block the potentiating
effect of BDNF in seven of the eight slices (Fig. 4, sixth column
from left). These results suggest that the long-lasting enhancing
effect of BDNF at 200 ng/ml on layer II/III responses may be mediated
through TrkB receptors.
Rapid penetration of BDNF into slices
Because the action of BDNF was found to be relatively rapid, there
was a question of how quickly BDNF, which was exogenously applied at
the perfusion rate of 200 ml/hr, penetrated into slices of the visual
cortex. To examine this question, slices perfused with the medium
containing BDNF at 20 or 200 ng/ml for 5 and 30 min and slices before
and after the BDNF application were stained immunohistochemically with
the antibody against BDNF. To minimize the possible difference in the
intensity of reactivity attributable to staining procedures, all of the
slices were processed simultaneously under identical conditions. After
the perfusion of slices with BDNF at 20 ng/ml for 5 min, the
immunoreactivity against exogenous BDNF was clearly recognizable in the
whole cortex (Fig. 5B,
top left). This antibody did not recognize endogenous BDNF
with the present staining procedures (Fig. 5A). After
perfusion with 200 ng/ml of BDNF for 30 min, the immunoreactivity of
slices was more intense (Fig. 5B, bottom right).
Five minutes after starting to wash out exogenous BDNF, the
immunoreactivity became very faint (data not shown) and almost
disappeared 25 min thereafter (Fig. 5C). The same series of
immunostaining was repeated in five slices for each test, and
essentially the same results as above were observed. This antibody
against BDNF fulfilled the following specificity tests: no recognizable
staining was observed in slices that had been perfused with BDNF at 200 ng/ml for 30 min when the antibody was replaced by normal chicken
serum, or the antibody was omitted from the immunohistochemical
procedures. These findings indicate that exogenous BDNF applied through
the medium could penetrate into slices within 5 min, under the present
perfusion condition, and could be washed out substantially within
another 5 min after the medium was changed to the standard one without
BDNF. This suggests that the long-lasting potentiation of responses
after cessation of the application may not be attributable to residues of exogenous BDNF in slices.
Fig. 5.
Rapid penetration of BDNF into slices.
Photomicrographs of sections obtained from slices before
(A), during (B), and after (C) perfusion with the medium containing BDNF at
the indicated concentration. Scale bars, 1 mm. All of the slices shown
here were processed simultaneously in identical staining conditions. Pia is upward and white matter is downward for each slice. In C, slices were subjected to immunohistochemistry 30 min
after the medium containing BDNF at 20 (left) and 200 (right) ng/ml was
changed to the standard medium.
[View Larger Version of this Image (59K GIF file)]
Enhancement of LTP by BDNF at the lower concentration
Although BDNF at the concentration of 20 ng/ml did not potentiate
layer II/III field responses evoked by test stimulation of layer IV at
0.1 Hz, it enhanced the magnitude of LTP induced by tetanic stimulation
of -burst type applied to layer IV of the cortex. An example is
shown in Figure 6. The application of BDNF did not significantly change layer II/III field potentials evoked
by test stimulation of layer IV (Fig. 6Ab). After
tetanic stimulation of layer IV, however, the postsynaptic component of responses was enhanced markedly (Fig. 6Ac), and this
enhancement lasted until the end of recordings (30 min after tetanus)
(Fig. 6B). The mean amplitudes of the postsynaptic
component for 16 slices were plotted against time in Figure
7B. The mean value 25-30 min
after tetanus was 123.2 ± 2.9% (SEM) of the control (Fig.
8, second column from left).
Without BDNF on the other hand, tetanic stimulation of the same
parameters induced a significant but weak LTP of layer II/III responses
(Fig. 7A). The mean value 25-30 min after tetanus was
107.8 ± 1.8% of the control (Fig. 8, left column).
Such a small magnitude of LTP was reported to be induced in the visual
cortex of rats without any antagonist for GABA receptors (Haruta et
al., 1994). The difference in the mean value for 25-30 min after
tetanus between slices without and with BDNF was statistically
significant (ANOVA; p < 0.0001). To test the
possibility that a contaminant in the vehicle solution might be
responsible for such an enhancing action of BDNF, the same procedures
as in the BDNF application were repeated with heat-inactivated BDNF.
LTP of the magnitude similar to that without BDNF was induced after
tetanic stimulation (Fig. 8, third column from left). Also,
NT-3 and NGF at the concentration of 20 ng/ml had no facilitatory
effect (Fig. 8, second from right and far right
columns). Finally, we tested whether the application of TrkB-IgG
or K252a itself could affect the induction of LTP and then whether they
could block the enhancing effect of BDNF on LTP. In 11 of the 13 slices
that had been incubated with TrkB-IgG, LTP was not induced by tetanic
stimulation of layer IV (Fig. 7E; also see Fig. 8,
fourth column from left). In 14 of the 15 slices tested with
K252a, LTP was not induced by tetanic stimulation of layer IV (Fig.
7C; also see Fig. 8, sixth column from left). In
another 13 slices that had been incubated with TrkB-IgG, tetanic stimulation was given to layer IV during the BDNF application, but it
turned out to be ineffective (Fig. 7F; also see Fig. 8, fifth column from left). In 11 of the 14 slices to which
BDNF was coapplied with K252a, tetanic stimulation was again
ineffective in inducing LTP (Fig. 7D; also see Fig. 8,
third column from right). These results suggest that the
enhancement of LTP by BDNF may be mediated through TrkB receptors, and
endogenous BDNF or another endogenous TrkB ligand may play a role in
LTP in the physiological condition.
Fig. 7.
Time courses of mean amplitude of field responses
after tetanic stimulation with or without BDNF, K252a, and TrkB-IgG.
Vertical bars indicate twice the SEM for the same group
of slices. Circles without vertical bars indicate that
the value of SEM was smaller than that of radius. A,
Tetanic stimulation was applied to layer IV of the cortex without any
drug at the time point indicated by arrow. B, C,
D, and F, Time courses of amplitude of responses after tetanus with BDNF and K252a, as indicated by horizontal bars. E, Time course of amplitude of responses
after tetanus. In E and F, slices were
preincubated with TrkB-IgG. For each slice, the mean of six consecutive
responses was calculated as percentage of that of 60 responses just
before the application of BDNF (B, F), K252a
(C, D), or tetanic stimulation
(A, E).
[View Larger Version of this Image (31K GIF file)]
Fig. 8.
Ratio of the amplitude of responses 25-30 min
after tetanus to that of control responses. Ordinate represents the
ratio of mean amplitude of the postsynaptic component of responses
calculated from 30 consecutive responses for 25-30 min after tetanus
to that of another 60 responses just before tetanus. Short
horizontal bars and vertical bars represent
means and twice the SEM for the same group of slices, respectively. The
number of slices used for each test is shown at the top of each column.
tet., Tetanic stimulation; inact. BDNF,
inactivated BDNF.
[View Larger Version of this Image (17K GIF file)]
DISCUSSION
Long-lasting potentiation of responses by the high dose
of BDNF
In the present study we found that BDNF at the concentration of
200 ng/ml potentiated layer II/III responses to test stimulation of
layer IV in most cases, and this potentiation lasted for at least 30 min after cessation of its application. Furthermore, this action of
BDNF was blocked by TrkB-IgG, which competes with TrkB receptors for
binding BDNF, and by K252a, which inhibits receptor tyrosine kinases.
These findings seem generally consistent with a previous study using
hippocampal slices, although BDNF at the concentration as low as 20 ng/ml was reported to be effective (Kang and Schuman, 1995). The
difference in the effective concentration of BDNF between the present
and previous results may be attributable to a regional difference in
density of TrkB. Hippocampus is known to express TrkB with the highest
density in the brain, although visual cortex also expresses it densely
(Klein et al., 1990; Merlio et al., 1992; Schoups et al., 1995; Cabelli
et al., 1996). Recently, however, Figurov et al. (1996) reported that
BDNF at 2 nM (corresponding to ~100 ng/ml) did not affect
basal synaptic transmission elicited by low-frequency stimulation (1 pulse/min) in the CA1 area of hippocampal slices. This discrepancy may
be attributable to a difference in types of recording chambers,
submerged and interface types, and/or in rates of perfusion of the
medium, as discussed below.
Rapid penetration of BDNF into slices
Recently, Patterson et al. (1996) reported that exogenously
applied BDNF at 100 ng/ml could penetrate only ~20 µm from the surface into hippocampal slices, even after 90 min of incubation. In
the present study, we clearly demonstrated that exogenous BDNF penetrated into the whole slice within 5 min after initiation of its
application. This discrepancy may be accounted for by the two
differences in experimental conditions between their study and ours. In
their study, hippocampal slices in an interface chamber were incubated
for a given period with the medium containing BDNF. In the present
study, on the other hand, BDNF was applied to submerged slices through
the medium, which flowed continuously at the rate of 200 ml/hr. In this
context it is to be noted that two other studies reporting the rapid
potentiating effects of BDNF with onset latency of ~5-15 min on
synaptic transmission in hippocampus and visual cortex also used slices
that were submerged in a stream of the medium at a flow rate of 250 and
120 ml/hr, respectively (Kang and Schuman, 1995; Carmignoto et al.,
1997). Thus, BDNF might penetrate more rapidly into submerged slices
that were exposed to continuous flow of the medium containing it than
into slices that were incubated with it in an interface chamber. The
other point to be noted is a structural difference. Visual cortical slices from young rats might be more permeable to BDNF than hippocampal slices from knockout mice that were used by Patterson et al.
(1996).
Enhancing action of BDNF on LTP
In the present study we found that BDNF at 20 ng/ml enhanced the
magnitude of LTP induced by tetanic stimulation of layer IV. This
effect might be attributable to an attenuation of inhibition so that
tetanic stimulation could induce a greater depolarization, because
GABAA receptor-mediated responses were reported to be suppressed by BDNF in rat hippocampus (Tanaka et al., 1997). Although we cannot completely exclude this possibility, the potentiating effect
of BDNF at least at 200 ng/ml may not be attributable to such an
indirect effect, because the initial slope of EPSCs or field potentials
is clearly enhanced by BDNF. Also, we found that the blockade of BDNF
action by TrkB-IgG or k252a completely suppressed the induction of weak
LTP without exogenous BDNF. The most straightforward explanation for
these findings is as follows: BDNF, whether endogenous or exogenous,
would lower the threshold of frequency for afferent stimulation to
induce LTP. Without the action of endogenous BDNF, for example, in the
case of application of TrkB-IgG or K252a, the high-frequency
stimulation such as -burst tetanus would become ineffective in
inducing LTP. When the concentration of BDNF increases to a certain
value, such as 200 ng/ml by the application of BDNF, it would decrease
the threshold so that 0.1 Hz stimulation could induce LTP. Although
there have been no available data suggesting mechanisms for a shift of
the threshold by BDNF, the recently reported results in coculture
preparation of Xenopus nerve/muscle cells by Stoop and Poo
(1996) seem to give a hint for such mechanisms. They demonstrated that
BDNF increases the concentration of
[Ca2+]i in presynaptic cytosol
concomitantly with synaptic potentiation, possibly through activation
of voltage-gated Ca2+ channels. If this is
applicable to synapses in visual cortical slices, the actions of BDNF,
such as lowering the threshold for LTP induction and enhancing the
magnitude of LTP, might be attributable to a larger or more prolonged
accumulation of Ca2+ in presynaptic terminals during
repetitive afferent stimulation with a higher concentration of
BDNF.
Ineffectiveness of NT-3 and NGF
In the present study we found that neither NT-3 nor NGF at 200 ng/ml is effective in potentiating layer II/III field responses evoked
by test stimulation of layer IV and that at 20 ng/ml both are also
ineffective in enhancing LTP induced by tetanic stimulation of layer
IV. The negative results with NGF seem consistent with previous results
in the other systems: NGF had no effects on basal synaptic transmission
or on LTP in the CA1 area of the hippocampus (Kang and Schuman, 1995;
Figurov et al., 1996), and it did not change synaptic activity in
coculture preparations of myocytes and spinal neurons (Lohof et al.,
1993). In line with these findings, previous studies demonstrated that
mRNA encoding TrkA, the high-affinity receptor for NGF, is confined to
a few dispersed populations of cholinergic neurons in the basal
forebrain and brain stem and not found in the cerebral cortex,
including visual cortex (Merlio et al., 1992; Gibbs and Pfaff,
1994).
With respect to NT-3, previous studies using cell culture preparations
of neurons and myocytes of Xenopus and of somatosensory cortical neurons of rats reported that this neurotrophin had
potentiating effects on synaptic activity (Ip et al., 1993; Lohof et
al., 1993; Kim et al., 1994, Wang et al., 1995). Using hippocampal
slices, Kang and Schuman (1995) also reported that NT-3 enhanced
synaptic transmission as BDNF did. On the other hand, Figurov et al.
(1996) reported that NT-3 did not promote the induction of LTP in
hippocampal slices prepared from young (postnatal day 12-13) rats,
although BDNF did. In this context it is to be noted that NT-3 and NGF were found to be ineffective in modulating the formation of ocular dominance columns in kitten visual cortex, whereas BDNF was effective (Cabelli et al., 1995). Thus, actions of NT-3 seem inconsistent among
species of animals and neural structures.
Relevance to plasticity of the visual system
The enhancement of LTP by BDNF seems to make sense in the light of
recent findings of developmental plasticity of function and structure
of visual cortex. The formation or segregation of ocular dominance
columns in the visual cortex of kittens is suggested to be dependent on
processes of consolidation of core axon terminals or retraction of
exuberant terminals (Callaway and Katz, 1992; Antonini and Stryker,
1993). This suggestion seems to be consistent with the recent
observations that the column formation in the visual cortex is impaired
by the application of BDNF (Cabelli et al., 1995; Hata et al., 1996),
because BDNF is known to increase their branching of axon terminals
(Cohen-Cory and Fraser, 1995). It is postulated that the branching
processes during the formation of ocular dominance columns may be
related to LTP of active, core synapses (Tsumoto, 1992; Singer, 1995).
Recently it has been suggested in hippocampus that BDNF stimulates the
synthesis of proteins for expression of LTP at or near activated
synapses (Kang and Schuman, 1996). Thus, the long-lasting potentiation
of active synapses by BDNF may lead to expansion of axon terminals or
dendrites through the protein synthesis. Therefore, it seems reasonable to assume that endogenous BDNF may play a role in activity-dependent modulation of synaptic connections in the developing visual cortex, as
suggested previously (Castrén et al., 1992b; Bozzi et al., 1995;
Cabelli et al., 1995; Galuske et al., 1996; Hata et al., 1996;
McAllister et al., 1996).
Recently Katz and his associates reported that another endogenous
ligand for TrkB, NT-4, has an antagonizing action on visual deprivation-induced atrophy of lateral geniculate neurons (Riddle et
al., 1995) and a facilitatory action on dendritic growth of some
cortical neurons (McAllister et al., 1995). In the present study we did
not test NT-4, and thus we could not determine whether the two types of
endogenous TrkB ligands have differential actions on cortical synaptic
transmission. In any case, the present result that the application of
TrkB-IgG prevented LTP from being generated by tetanic stimulation
suggests that BDNF and/or NT-4 are normally present in limited amounts
and may facilitate potentiation or consolidation of active synapses in
the developing visual cortex.
FOOTNOTES
Received April 23, 1997; revised June 20, 1997; accepted June 23, 1997.
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 Regeneron Pharmaceutical Co., Kyowa
Hakko Kogyo Co., and Genentech Inc. for kind gifts of human recombinant
BDNF, K252a, and TrkB-IgG, respectively.
Correspondence should be addressed to Dr. Tadaharu Tsumoto, Department
of Neurophysiology, Biomedical Research Center, Osaka University
Medical School, Yamadaoka, Suita City, 565 Japan.
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C. Itami, F. Kimura, T. Kohno, M. Matsuoka, M. Ichikawa, T. Tsumoto, and S. Nakamura
Brain-derived neurotrophic factor-dependent unmasking of """silent""" synapses in the developing mouse barrel cortex
PNAS,
October 28, 2003;
100(22):
13069 - 13074.
[Abstract]
[Full Text]
[PDF]
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R. A. Wardle and M.-m. Poo
Brain-Derived Neurotrophic Factor Modulation of GABAergic Synapses by Postsynaptic Regulation of Chloride Transport
J. Neurosci.,
September 24, 2003;
23(25):
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[Abstract]
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[PDF]
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J. A. Gorski, S. R. Zeiler, S. Tamowski, and K. R. Jones
Brain-Derived Neurotrophic Factor Is Required for the Maintenance of Cortical Dendrites
J. Neurosci.,
July 30, 2003;
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[Abstract]
[Full Text]
[PDF]
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B. Jiang, Y. Akaneya, Y. Hata, and T. Tsumoto
Long-Term Depression Is Not Induced by Low-Frequency Stimulation in Rat Visual Cortex In Vivo: A Possible Preventing Role of Endogenous Brain-Derived Neurotrophic Factor
J. Neurosci.,
May 1, 2003;
23(9):
3761 - 3770.
[Abstract]
[Full Text]
[PDF]
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A. Bartoletti, L. Cancedda, S. W. Reid, L. Tessarollo, V. Porciatti, T. Pizzorusso, and L. Maffei
Heterozygous Knock-Out Mice for Brain-Derived Neurotrophic Factor Show a Pathway-Specific Impairment of Long-Term Potentiation But Normal Critical Period for Monocular Deprivation
J. Neurosci.,
December 1, 2002;
22(23):
10072 - 10077.
[Abstract]
[Full Text]
[PDF]
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A. Balkowiec and D. M. Katz
Cellular Mechanisms Regulating Activity-Dependent Release of Native Brain-Derived Neurotrophic Factor from Hippocampal Neurons
J. Neurosci.,
December 1, 2002;
22(23):
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[Abstract]
[Full Text]
[PDF]
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M. Canossa, E. Giordano, S. Cappello, C. Guarnieri, and S. Ferri
Nitric oxide down-regulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons
PNAS,
February 20, 2002;
(2002)
42504299.
[Abstract]
[Full Text]
[PDF]
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T. Numakawa, S. Yamagishi, N. Adachi, T. Matsumoto, D. Yokomaku, M. Yamada, and H. Hatanaka
Brain-derived Neurotrophic Factor-induced Potentiation of Ca2+ Oscillations in Developing Cortical Neurons
J. Biol. Chem.,
February 15, 2002;
277(8):
6520 - 6529.
[Abstract]
[Full Text]
[PDF]
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F. M. Rossi, R. Sala, and L. Maffei
Expression of the Nerve Growth Factor Receptors TrkA and p75NTR in the Visual Cortex of the Rat: Development and Regulation by the Cholinergic Input
J. Neurosci.,
February 1, 2002;
22(3):
912 - 919.
[Abstract]
[Full Text]
[PDF]
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A. H. Kossel, S. B. Cambridge, U. Wagner, and T. Bonhoeffer
A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation
PNAS,
November 20, 2001;
(2001)
251326998.
[Abstract]
[Full Text]
[PDF]
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H. W. Tao and M.-m. Poo
Retrograde signaling at central synapses
PNAS,
September 25, 2001;
98(20):
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[Abstract]
[Full Text]
[PDF]
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K. Kohara, A. Kitamura, M. Morishima, and T. Tsumoto
Activity-Dependent Transfer of Brain-Derived Neurotrophic Factor to Postsynaptic Neurons
Science,
March 23, 2001;
291(5512):
2419 - 2423.
[Abstract]
[Full Text]
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N. Taniguchi, N. Takada, F. Kimura, and T. Tsumoto
Actions of brain-derived neurotrophic factor on evoked and spontaneous EPSCs dissociate with maturation of neurones cultured from rat visual cortex
J. Physiol.,
September 15, 2000;
527(3):
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[Abstract]
[Full Text]
[PDF]
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M. M. Bolton, A. J. Pittman, and D. C. Lo
Brain-Derived Neurotrophic Factor Differentially Regulates Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures
J. Neurosci.,
May 1, 2000;
20(9):
3221 - 3232.
[Abstract]
[Full Text]
[PDF]
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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]
[PDF]
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F.-Q. Liang, G. Allen, and D. Earnest
Role of Brain-Derived Neurotrophic Factor in the Circadian Regulation of the Suprachiasmatic Pacemaker by Light
J. Neurosci.,
April 15, 2000;
20(8):
2978 - 2987.
[Abstract]
[Full Text]
[PDF]
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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]
[PDF]
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C. Lodovichi, N. Berardi, T. Pizzorusso, and L. Maffei
Effects of Neurotrophins on Cortical Plasticity: Same or Different?
J. Neurosci.,
March 15, 2000;
20(6):
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[Abstract]
[Full Text]
[PDF]
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A. F. Ernst, G. Gallo, P. C. Letourneau, and S. C. McLoon
Stabilization of Growing Retinal Axons by the Combined Signaling of Nitric Oxide and Brain-Derived Neurotrophic Factor
J. Neurosci.,
February 15, 2000;
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1458 - 1469.
[Abstract]
[Full Text]
[PDF]
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J. Liu, K. Fukunaga, H. Yamamoto, K. Nishi, and E. Miyamoto
Differential Roles of Ca2+/Calmodulin-Dependent Protein Kinase II and Mitogen-Activated Protein Kinase Activation in Hippocampal Long-Term Potentiation
J. Neurosci.,
October 1, 1999;
19(19):
8292 - 8299.
[Abstract]
[Full Text]
[PDF]
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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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L. Ma, G. Reis, L. F. Parada, and E. M. Schuman
Neuronal NT-3 Is not Required For Synaptic Transmission or Long-Term Potentiation in Area CA1 of the Adult Rat Hippocampus
Learn. Mem.,
May 1, 1999;
6(3):
267 - 275.
[Abstract]
[Full Text]
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S. Kinoshita, H. Yasuda, N. Taniguchi, R. Katoh-Semba, H. Hatanaka, and T. Tsumoto
Brain-Derived Neurotrophic Factor Prevents Low-Frequency Inputs from Inducing Long-Term Depression in the Developing Visual Cortex
J. Neurosci.,
March 15, 1999;
19(6):
2122 - 2130.
[Abstract]
[Full Text]
[PDF]
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Y.-X. Li, Y. Zhang, H. A. Lester, E. M. Schuman, and N. Davidson
Enhancement of Neurotransmitter Release Induced by Brain-Derived Neurotrophic Factor in Cultured Hippocampal Neurons
J. Neurosci.,
December 15, 1998;
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10231 - 10240.
[Abstract]
[Full Text]
[PDF]
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M. Kokaia, F. Asztely, K. Olofsdotter, C. B. Sindreu, D. M. Kullmann, and O. Lindvall
Endogenous Neurotrophin-3 Regulates Short-Term Plasticity at Lateral Perforant Path-Granule Cell Synapses
J. Neurosci.,
November 1, 1998;
18(21):
8730 - 8739.
[Abstract]
[Full Text]
[PDF]
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E. S. Levine, R. A. Crozier, I. B. Black, and M. R. Plummer
Brain-derived neurotrophic factor modulates hippocampal synaptic transmission by increasing N-methyl-D-aspartic acid receptor activity
PNAS,
August 18, 1998;
95(17):
10235 - 10239.
[Abstract]
[Full Text]
[PDF]
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M. E. Morrison and C. A. Mason
Granule Neuron Regulation of Purkinje Cell Development: Striking a Balance Between Neurotrophin and Glutamate Signaling
J. Neurosci.,
May 15, 1998;
18(10):
3563 - 3573.
[Abstract]
[Full Text]
[PDF]
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W Haubensak, F Narz, R Heumann, and V Lessmann
BDNF-GFP containing secretory granules are localized in the vicinity of synaptic junctions of cultured cortical neurons
J. Cell Sci.,
January 6, 1998;
111(11):
1483 - 1493.
[Abstract]
[PDF]
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M. Canossa, E. Giordano, S. Cappello, C. Guarnieri, and S. Ferri
Nitric oxide down-regulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons
PNAS,
March 5, 2002;
99(5):
3282 - 3287.
[Abstract]
[Full Text]
[PDF]
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Y. Yin, G. M. Edelman, and P. W. Vanderklish
The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes
PNAS,
February 19, 2002;
99(4):
2368 - 2373.
[Abstract]
[Full Text]
[PDF]
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A. H. Kossel, S. B. Cambridge, U. Wagner, and T. Bonhoeffer
A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation
PNAS,
December 4, 2001;
98(25):
14702 - 14707.
[Abstract]
[Full Text]
[PDF]
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Substance via MeSH
