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The Journal of Neuroscience, October 15, 1999, 19(20):9090-9097
Presynaptic Long-Term Potentiation in Corticothalamic
Synapses
Manuel A.
Castro-Alamancos and
Maria
E.
Calcagnotto
Department of Neurology and Neurosurgery, Montreal Neurological
Institute, McGill University, Montreal, Quebec H3A2B4, Canada
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ABSTRACT |
The thalamus and neocortex are two highly organized and complex
brain structures that work in concert with each other. The largest
synaptic input to the thalamus arrives from the neocortex via
corticothalamic fibers. Using brain slices, we describe long-term potentiation (LTP) in corticothalamic fibers contacting the ventrobasal thalamus. Corticothalamic LTP is input-specific, NMDA
receptor-independent, and reversible. The induction of corticothalamic
LTP is entirely presynaptic and Ca2+-dependent. The
expression of corticothalamic LTP is associated with a decrease in
paired-pulse facilitation (PPF) and blocked by an inhibitor of the
cAMP-dependent protein kinase A (PKA). Consistent with an
involvement of cAMP and PKA, activation of adenylyl cyclase induced a
synaptic enhancement that was associated with a decrease in PPF and
occluded LTP. Corticothalamic LTP may serve to enhance the efficacy of
cortico-cortical communication via the thalamus and/or to mediate
experience-dependent long-term modifications of thalamocortical
receptive fields.
Key words:
thalamus; neocortex; synaptic plasticity; cAMP; protein
kinase A; long-term potentiation; long-term depression
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INTRODUCTION |
Almost all of the information that
reaches the neocortex arrives from the thalamus via thalamocortical
fibers. In return, the thalamus receives a massive feedback from the
neocortex via corticothalamic fibers. The number of corticothalamic
fibers is one order of magnitude larger than the number of
thalamocortical axons (Sherman and Guillery, 1996 ), and cortical
afferents are the most abundant input to the thalamus (Guillery, 1969).
In the somatosensory system, the most corticothalamic fibers originate in layer VI and send reciprocal connections to the ventrobasal thalamus
(ventroposteromedial and lateral nuclei), leaving a fiber collateral in
the reticular nucleus (Zhang and Deschenes, 1997). Corticothalamic
fibers from layer VI act on distal dendrites of thalamic neurons,
forming a fine plexus with simple branching and fine synaptic boutons
(Robson, 1983). In addition, there is a group of corticothalamic fibers
that originates in layer V and reaches the posterior nucleus of the
thalamus, without innervating the ventrobasal thalamus or reticular
nucleus (Hoogland, 1991; Ojima, 1994; Bourassa et al., 1995; Levesque
et al., 1996; Vidnyansky et al., 1996). Corticothalamic synapses use
glutamate as their neurotransmitter, which activates both non-NMDA and
NMDA ionotropic glutamate receptors (Deschenes and Hu, 1990; Scharfman
et al., 1990; Eaton and Salt, 1996; Kao and Coulter, 1997; Steriade et al., 1997; Turner and Salt, 1998). Metabotropic glutamate
receptor-mediated responses have been described at these synapses in
some studies (McCormick and von Krosigk, 1992; Eaton and Salt, 1996;
Golshani et al., 1998), but not in others (Kao and Coulter, 1997;
Turner and Salt, 1998). Repetitive stimulation of corticothalamic
fibers produces short-term facilitation of EPSPs in thalamic
neurons (Frigyesi, 1972; Steriade and Wyzinski, 1972; Tsumoto et al., 1978; Deschenes and Hu, 1990; Lindstrom and Wrobel, 1990; Scharfman et
al., 1990; McCormick and von Krosigk, 1992; Steriade and Timofeev, 1997).
The functional role of corticothalamic pathways is unknown. They may
play a role in modifying the size, strength, and selectivity of
thalamocortical receptive fields (Yuan et al., 1985; Diamond, 1995;
Weinberger, 1995; Ergenzinger et al., 1998) and/or serve to establish
cortico-cortical communication via the thalamus (Guillery, 1995). In
all these instances, a mechanism for bi-directional activity-dependent
long-term synaptic plasticity in corticothalamic synapses would be
advantageous. It would provide the capacity to modify the effectiveness
with which the neocortex can influence the thalamus. The most
characteristic forms of long-term synaptic plasticity are long-term
potentiation (LTP) and long-term depression (LTD). Both LTP and LTD
have been studied in numerous synapses (Bliss and Collingridge, 1993;
Bear and Malenka, 1994; Nicoll and Malenka, 1995), but they have yet to
be described in the thalamus. We therefore performed a series of
experiments to explore long-term synaptic plasticity in corticothalamic fibers.
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MATERIALS AND METHODS |
Thalamocortical slices were prepared from adult ( 7 weeks)
BALB/C mice according to the methods described by Agmon and Connors (1991). Slices were cut in ice-cold buffer using a vibratome and kept in a holding chamber for a least 1 hr. Experiments were performed in an interface chamber at 32°C. The slices were perfused constantly (1-1.5 ml/min) with artificial CSF (ACSF) containing (in
mM): NaCl 126, KCl 3, NaH2Po4 1.25, NaHCO3 26, MgSO4 7H2O
1.3, dextrose 10, and CaCL2
2H2O 2.5. The ACSF was bubbled with 95%
O2 and 5% CO2. Synaptic
responses were induced using a concentric stimulating electrode
(Frederick Haer Co.) placed in the thalamic radiation. The stimulus
consisted of a 200 µsec pulse of <50 µA. The ventrobasal thalamus
was easily and clearly identifiable with a dissecting microscope. Field
recordings were made using a low-impedance pipette (~0.5 M ) filled
with ACSF or with ACSF containing 400 µM bicuculline methbromide (BMI). Intracellular recordings were performed using sharp
electrodes (80-120 M) filled with 3 M
potassium-acetate. The test stimulus was delivered at 0.05 Hz and was
either single or a pair with a 50 msec interstimulus interval to
evaluate paired-pulse facilitation (PPF). The data are expressed as
mean ± SEM as a percentage of the baseline amplitude or slope.
For single experiments, which represent typical examples, every
response at 0.05 Hz is displayed.
The following drugs were stored as concentrated stock solutions and
were diluted to the desired concentration using ACSF: 50 mM
forskolin and 5 mM 1,9-dideoxyforskolin (dissolved in DMSO; Research Biochemicals, Natick, MA), 50 mM Rp-cAMPs
(dissolved in water; BIOMOL">Biomol, Plymouth Meeting, PA), 20 mM
6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) (dissolved in
water; Research Biochemicals), 50 mM
±-2-amino-5-phosphonovaleric acid (APV) (dissolved in water; Research
Biochemicals), 40 mM BMI (dissolved in water; Sigma, St.
Louis, MO), 50 mM cyclothiazide (dissolved in DMSO;
Research Biochemicals), and  -methyl-4-carboxyphenylglycine (MCPG)
(dissolved in the ACSF to 1 mM; Research Biochemicals). All
drugs were tested using bath application, although some drugs were also
tested with local application. BMI was applied in either the bath (40 µM) or the extracellular recording pipette by filling the
recording pipette with ACSF containing BMI (400 µM). CNQX
and APV were applied in the bath (10-20 and 50-100 µM,
respectively) or by using a low-impedance (~0.5 M) pipette filled
with ACSF containing these drugs (100 and 250 µM,
respectively). The drug-containing pipette was placed adjacent (~500
µm) to the recording electrode, and the action of the drugs was
monitored from the recording electrode.
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RESULTS |
LTP in corticothalamic fibers
Field and intracellular potentials were recorded from neurons of
the ventrobasal thalamus in brain slices of adult mice (Fig. 1A). Orthodromic
stimuli applied to the thalamic radiation evoked a negative potential
in field recordings from populations of neurons and an EPSP in
intracellular recordings from individual neurons of the ventrobasal
thalamus (Fig. 1B). The field and intracellular EPSPs
reflected a monosynaptic excitatory connection between corticothalamic fibers and neurons in the ventrobasal thalamus. This assertion is based
on the following arguments. (1) The ventrobasal thalamus does not
contain GABAergic interneurons, but it receives GABAergic input from
the reticular nucleus (nRT), which is activated by corticothalamic
fibers. To avoid the contribution of disynaptic IPSPs on
corticothalamic responses, GABAA receptors were
blocked locally by including BMI (400 µM) in
the low-impedance (~0.5 M) extracellular recording electrode or in
the bath (40 µM). (2) Stimulation of the
thalamic radiation may activate thalamocortical fibers and thus the
neocortex. To ensure that activity in cortical circuits did not feed
back to the thalamus, we severed all connections between thalamus and
neocortex with a cut just below the cortical white matter (Fig.
1A). (3) Stimulation of the thalamic radiation could
antidromically discharge neurons in the ventrobasal thalamus by
directly activating their axons. However, antidromic activation cannot
contribute to the recorded EPSPs because of the lack of recurrent
connections between thalamic ventrobasal neurons. (4) Application of
AMPA and NMDA receptor antagonists abolishes the field potential (see
Fig. 5A). A short-latency (1-2 msec from the
stimulus artifact) negativity resistant to glutamate receptor antagonists was observed in many extracellular recordings (see Fig. 5),
and it was abolished by TTX (1 µM; data not
shown). This short-latency non-synaptic component, the fiber volley,
was monitored in many experiments as an index of fiber excitability.
The field potential was also dependent on extracellular
Ca+2 (see Fig. 5). (5) Consistent with a
monosynaptic connection, both the intracellular and extracellular EPSPs
have a constant and short latency of ~3 msec, and both follow
high-frequency (50 Hz) stimulation without failure. As for other
monosynaptic excitatory connections, paired-pulse stimulation produces
strong facilitation in both the field and intracellularly recorded
EPSPs (Fig. 1B). Facilitation is a consistent finding
among studies that test corticothalamic pathways (Frigyesi, 1972;
Steriade and Wyzinski, 1972; Tsumoto et al., 1978; Deschenes and Hu,
1990; Lindstrom and Wrobel, 1990; Scharfman et al., 1990; McCormick and
von Krosigk, 1992; Steriade and Timofeev, 1997). The only
corticothalamic input to the ventrobasal thalamus arises from
neocortical neurons in layer VI (Bourassa et al., 1995). Based on these
arguments, we conclude that the synaptic responses we recorded in
response to stimulation of the thalamic radiation result from the
depolarization of ventrobasal neurons caused by the release of
glutamate from corticothalamic fibers originating in layer VI
neurons.
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Figure 1.
Intracellular and field corticothalamic EPSPs and
LTP. A, Diagram of the corticothalamic slice
preparation. The typical positions of the stimulating and recording
electrodes are shown. The stimulating electrode is placed in the
thalamic radiation. The recording electrode is placed in the
ventrobasal thalamus (VB). To ensure that activity in
neocortical circuits did not feed back to the thalamus, all connections
between thalamus and neocortex were severed with a cut below the
cortical white matter. B, Paired-pulse facilitation of
corticothalamic EPSPs. Intracellular and field EPSPs evoked in the
ventrobasal thalamus in response to a pair of stimuli delivered in the
thalamic radiation with a 50 msec interstimulus interval
(ISI). C, LTP of corticothalamic
EPSPs. Effect of 10 Hz stimulation (600 pulses in 6 trains of 100 pulses each delivered with a 10 sec interval between trains) on the
amplitude of an intracellular EPSP recorded from the ventrobasal
thalamus in response to stimulation of the thalamic radiation. The
input resistance of the same neuron was also monitored with a 50 msec
current pulse. Test stimuli were applied at 0.05 Hz, and all responses
are displayed.
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We first explored the competence of corticothalamic EPSPs to undergo
LTP. To induce LTP, 600 pulses were delivered in six trains of 100 pulses each with an interval between trains of 10 sec. Trains consisted
of 1 or 10 Hz. After 10 Hz stimulation, a lasting synaptic enhancement
(LTP, >35 min) developed in both the field and the intracellular EPSP
(Fig. 1C). Typically, 10 Hz stimulation produces a strong
several-fold increase in the synaptic response, which decays within the
next few minutes to a stable enhancement of ~180% of the baseline.
In a few experiments (n = 3), LTP was followed for 2 hr
without decrement. LTP is demonstrated in both the field and
intracellular EPSPs (Figs. 1C,
2A). Intracellular recordings from ventrobasal thalamic neurons demonstrate that LTP is
not associated with a change in input resistance (measured by applying
a current pulse; 50 msec, 0.2 nA; n = 4) (Fig.
1C). During intracellular recordings (n = 10), the amplitude of the evoked EPSP was set at an amplitude that did
not reach threshold to trigger a low-threshold calcium spike, and none
of the neurons included in the study were antidromically activated with
the intensities used. Field recordings established that LTP is not
associated with a change in fiber excitability, as determined by
measuring the fiber volley (100 ± 3% of the baseline fiber
volley amplitude measured 35 min after LTP induction; n = 4). After LTP has been induced, with 10 Hz stimulation, subsequent
activation of the same corticothalamic fibers at 1 Hz (using the same
number of stimuli) produces a lasting synaptic depression (LTD) or
depotentiation that reverses LTP (Fig. 2A). For the
remainder of the study, we investigated the properties of
corticothalamic LTP induced by 10 Hz stimulation.
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Figure 2.
Corticothalamic LTP is reversible and
input-specific. A, Stimulation (10 Hz; 600 pulses) produces LTP that is expressed as a change in the slope
and amplitude of the field potential. Application of 1 Hz stimulation
(600 pulses) 30 min after LTP induction reverses LTP. The
numbers in the graph correspond to the field recordings
shown above. B, Responses were evoked by two stimulating
electrodes placed in the thalamic radiation and recorded from a single
electrode in the ventrobasal thalamus. Stimulation (10 Hz) delivered to
one of the electrodes (S1; open circles)
produced LTP but had no effect on the responses evoked from the other
stimulating electrode (S2; closed
circles). The amplitude of the field potential was
measured.
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The next experiment sought to investigate whether LTP was
input-specific. Two stimulating electrodes were placed in the thalamic radiation on two independent sets of fibers. A population of thalamic neurons was monitored using a single recording electrode. To ensure that the electrodes activated independent sets of fibers, we tested for
paired-pulse interactions between them. When two stimuli are delivered
with a 50 msec interval through the same electrode, they activate the
same set of fibers and produce robust synaptic facilitation. In
contrast, if the first stimulus is delivered through one electrode and
the second stimulus (50 msec latter) is delivered through another
electrode, facilitation to the second stimulus would only occur if both
electrodes activate the same set of fibers. Thus, by ensuring that
facilitation to the second stimulus delivered through the second
electrode does not occur, we can assume that the two electrodes
activate different fibers. After determining that the two electrodes
activated independent sets of fibers, we applied 10 Hz stimulation to
one of them. LTP developed only in the pathway in which the 10 Hz
stimulation was applied (n = 5) (Fig.
2B). This indicates that corticothalamic LTP is
input-specific.
Placing BMI locally in the recording pipette (400 µM) or
in the bath (40 µM) tested the effect of blocking
GABAA receptors on LTP induction. In other areas,
such as the hippocampus (Schaffer collaterals) and the neocortex, the
induction of LTP is eased by GABAA receptor block
(Wigstrom and Gustafsson, 1983; Castro-Alamancos et al., 1995).
However, we found no significant effect of BMI on the induction of LTP
in corticothalamic fibers (Fig.
3B). The average enhancement
in the presence of BMI was 183% of the baseline, which is not
significantly different from the average synaptic enhancement observed
without BMI (n = 5; 35 min after LTP induction; t test; NS) (Fig. 3A). Despite this
finding, we used local BMI application for the remainder of the
experiments to be certain that our manipulations were not mediated
through changes in disynaptic GABAA IPSPs.
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Figure 3.
Corticothalamic LTP is not affected by NMDA
receptor block or disinhibition. A, Summary of
experiments (n = 5) showing the effects of 10 Hz
stimulation on the amplitude of corticothalamic field potentials in
normal ACSF (Control). B, Summary
of experiments (n = 5) in which 10 Hz stimulation
was applied in the presence of BMI (400 µM) in the field
recording pipette. C, Summary of experiments
(n = 5) in which 10 Hz stimulation was applied in
the presence of APV (100 µM) in the bath. Data correspond
to the amplitude of the field potential expressed as the mean ± SEM of every response at 0.05 Hz. Stimulation (10 Hz) was applied after
a 10 min baseline.
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We then examined whether the induction of LTP required the activation
of NMDA receptors or metabotropic glutamate receptors. LTP induction
was not significantly affected by bath application (100 µM) of the NMDA antagonist APV (Fig. 3C).
Neither the initial large potentiation nor the persistent enhancement
of the corticothalamic field potential were significantly affected in
slices treated with APV compared with control slices (n = 5; 35 min after LTP induction; t test; NS). The
effectiveness of APV was verified by demonstrating that Schaffer
collateral LTP was blocked in the same slices (100 Hz tetanus for 1 sec
repeated four times at 10 sec intervals). LTP induction was also not
significantly affected by bath application (1 mM)
of the metabotropic glutamate receptor antagonist MCPG
(n = 4; 178 ± 9% of baseline responses; 35 min after LTP induction). Moreover, application of MCPG had no significant effect on the baseline field potential response (data not shown).
LTP was further characterized by testing its effects on PPF. PPF is a
well defined presynaptic process in which residual
Ca2+ influx after the first of two stimuli
results in an enhancement of transmitter release in response to the
second stimulus (Zucker, 1989). In the mossy fibers of hippocampus and
in the parallel fibers of cerebellum in which LTP is presynaptic and
not dependent on NMDA receptor activation, LTP leads to a persistent
depression of PPF (Zalutsky and Nicoll, 1990; Salin et al., 1996). We
found that LTP in corticothalamic fibers is accompanied by a persistent reduction of PPF (Fig. 4). The reduction
in PPF was very large during the initial minute of strong potentiation
after the 10 Hz stimulation. During the stable synaptic enhancement,
PPF was also significantly reduced. The average PPF 35 min after LTP
induction was 70 ± 5% of the baseline (n = 5).
Because PPF changes can be caused by changes in the desensitization of
AMPA receptors (Wang and Kelly, 1996), we examined LTP and PPF
in the presence of cyclothiazide (50 µM), which
prevents the desensitization of AMPA receptors. In every case tested
(n = 3), we observed that PPF was reduced during LTP in
the presence of cyclothiazide (72 ± 7% of baseline) to a similar
degree than control slices (70 ± 5% of baseline). These results
suggest that the expression of LTP in corticothalamic synapses is
presynaptic.
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Figure 4.
Corticothalamic LTP occludes PPF.
A, Changes in paired-pulse facilitation during LTP. The
field recordings show the effect of paired-pulse stimulation (50 msec
interstimulus interval) before and 35 min after LTP induction. The
field recordings correspond to the numbers shown in
B. On the right, the second responses of
the pair are scaled to reveal changes in PPF. Scaling is accomplished
by changing the y-axis scale until the second responses
of the pairs are equal in amplitude before and during LTP.
B, Paired pulses (50 msec) were delivered at 0.05 Hz
before and after the induction of LTP. Shown is the amplitude of the
field potential to the first pulse (top) and the change
in PPF associated with LTP displayed as a percentage of the baseline
PPF (bottom).
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Corticothalamic LTP induction does not require postsynaptic
activation but requires calcium
The results show that corticothalamic LTP is input-specific, not
dependent on the activation of NMDA receptors or disinhibition, and
proceeds with a persistent occlusion of PPF. We next sought to test
whether there is an actual postsynaptic involvement in the induction of
corticothalamic LTP. To address this issue, we applied 10 Hz
stimulation in the presence of NMDA and non-NMDA receptor antagonists
(100 µM CNQX and 250 µM APV were applied using a pipette placed adjacent to the recording electrode). Figure 5 shows such an experiment. An initial
application of the glutamate receptor antagonists completely blocks
evoked postsynaptic activity but leaves intact the fiber volley. Upon
removal of the antagonists, the responses recover to their baseline
amplitudes. The antagonists were applied again, but in this case, 10 Hz
stimulation was delivered during the receptor blockade. Upon removal of
the antagonists, the synaptic response did not return to control levels
but increased to a stable enhancement (198 ± 9% of baseline
after 1 hr; n = 5) (Fig. 5B). Moreover, LTP
induced during postsynaptic block was accompanied by a significant
reduction of PPF. A subsequent block of postsynaptic activity, which
revealed again the fiber volley, demonstrates that LTP is not
accompanied by a change in fiber excitability (Fig.
5A,C). These results show that
postsynaptic activity is not required for the induction of
corticothalamic LTP.
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Figure 5.
Corticothalamic LTP induction does not require
postsynaptic activation but requires calcium. A, Field
responses correspond to the experiment shown in C.
B, Comparison of the effects of previous application of
glutamate receptor antagonists (CNQX and APV) or 0 Ca2+ ACSF during which 10 Hz stimulation was applied
(black) or was not applied (white). Shown
are the amplitudes of the responses (mean ± SEM;
n = 5-7) recorded 1 hr after recovery from
complete field EPSP block (induced by CNQX plus APV or by 0 Ca2+ ACSF), represented as the percentage of the
baseline amplitude (before field EPSP block). C, A
typical experiment showing that, after a brief application of CNQX and
APV, which completely blocks postsynaptic responses (compare
1 and 2 in A), field EPSPs
return to their baseline amplitudes. A subsequent application of CNQX
and APV during which 10 Hz stimulation was applied produces LTP that is
associated with a decrease in PPF. Subsequent application of CNQX and
APV serves to demonstrate that the fiber volley did not change during
LTP (compare 2 and 4 in
A). D, Application of 10 Hz stimulation
during complete block of synaptic transmission caused by 0 Ca2+ ACSF did not produce LTP. A subsequent
application of 10 Hz stimulation in the presence of extracellular
Ca+2 induces LTP. Data are presented as the
percentage of the baseline field potential amplitude.
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The dependence of corticothalamic LTP on extracellular
Ca2+ was also examined. Removal of
Ca2+ from the ACSF (0 Ca2+ and 4 mM
Mg2+ ACSF) blocked corticothalamic
synaptic transmission (Fig. 5D). Application of 10 Hz
stimulation during complete block of synaptic transmission did not
produce LTP; responses returned to baseline levels after restoration of
Ca2+ (102 ± 6% of baseline;
n = 7) (Fig. 5B). Subsequent application of
10 Hz stimulation in the presence of extracellular
Ca2+ induces LTP (Fig. 5D).
This finding, together with the lack of effect of blocking postsynaptic
depolarization, indicates that a presynaptic rise in
Ca2+ is necessary for the induction of LTP.
Expression of corticothalamic LTP involves cAMP and protein
kinase A
LTP, which is NMDA receptor-independent and induced by a
presynaptic increase in Ca2+, has been
described in hippocampal mossy fibers and cerebellar parallel fibers
(Zalutsy and Nicoll, 1990; Huang et al., 1994; Weisskopf et al.,
1994; Salin et al., 1996). These forms of LTP and a similar type found
in the lateral amygdala (Huang and Kandel, 1998) have been shown to
depend on cAMP. To test the role of cAMP in corticothalamic LTP, we
applied forskolin, which directly activates adenylyl cyclase and
elevates cAMP levels. Forskolin enhanced corticothalamic synaptic
responses, and this enhancement was long-lasting (at least 2 hr)
despite the brief application (15 min; n = 5) (Fig.
6). Similar to LTP induced with 10 Hz
stimulation, forskolin-induced enhancement was associated with a
decrease in PPF and with no change in the fiber volley (Fig. 6). The
forskolin analog dideoxyforskolin (50 µM),
which does not activate adenylyl cyclase but mimics other effects of
forskolin, did not induce a lasting synaptic enhancement (103 ± 5% of baseline; 35 min after application; n = 3).
Thus, direct activation of adenylyl cyclase mimics the effect of 10 Hz
stimulation on corticothalamic fibers.
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Figure 6.
Forskolin enhances corticothalamic field
potentials and occludes PPF and LTP. A, Change in
paired-pulse facilitation during forskolin-induced enhancement. The
field recordings represent the effect of two stimuli delivered with a
50 msec interval (ISI) before and 35 min after
forskolin-induced enhancement. The field recordings correspond to the
numbers shown in B. On the
right, the second responses of the pair are scaled to
reveal changes in PPF. B, Paired-pulse stimulation (50 msec) was delivered at 0.05 Hz before, during, and after application of
forskolin (50 µM). Plotted is the amplitude of the field
potential to the first response (top) and the change in
PPF (bottom), displayed as a percentage of the baseline
PPF. During forskolin-induced enhancement, the evoked response was
reduced to the baseline amplitude by decreasing the stimulus, and 10 Hz
stimulation was applied. The stimulus amplitude was restored, and 10 Hz
stimulation was delivered again. C, Summary of five
experiments (mean ± SEM) in which forskolin enhanced
corticothalamic field potentials.
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If forskolin-induced LTP and 10 Hz-induced LTP share the same
underlying mechanisms, elevation of cAMP by forskolin should occlude
further potentiation by 10 Hz stimulation of corticothalamic fibers. To
test this, we tried to induce LTP in corticothalamic fibers after
forskolin had enhanced synaptic transmission. As shown in Figure 6,
after application of forskolin, 10 Hz stimulation failed to induce LTP
(106 ± 9% of baseline; 35 min after 10 Hz stimulation;
n = 4). LTP was not observed either if the 10 Hz stimulation was applied after returning the field potential to the pre-forskolin baseline amplitude or if it was applied at the post-forskolin amplitude (Fig. 6). We were sure that these slices were
capable of generating LTP because 10 Hz stimulation was tested before
forskolin in a different set of corticothalamic fibers from the same
slice or in other slices from the same animal, confirming that
corticothalamic LTP could be generated.
Because cAMP elevation is able to induce LTP in corticothalamic fibers,
we tested whether an inhibitor of protein kinase A (PKA) blocked LTP.
Bath application of Rp-cAMPs (50 µM), a potent and
competitive PKA inhibitor, had no effect on baseline synaptic transmission; however, LTP was not generated by 10 Hz stimulation (n = 6) (Fig. 7). This
effect was partially reversible in some experiments because application
of 10 Hz stimulation after washout of the drug was able to induce LTP
(130 ± 9% of baseline compared with 180% in control
slices).
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Figure 7.
Corticothalamic LTP is blocked by a PKA inhibitor.
A, The field recordings correspond to the experiment
shown in B. B, Rp-cAMPs, an inhibitor of
PKA, blocked corticothalamic LTP. Responses were evoked at 0.05 Hz, and
Rp-cAMPs was included (50 µM) in the bath without any
effect on the baseline after a 25 min application of Rp-cAMPs 10 Hz
stimulation was applied, and LTP was not induced. In this experiment, a
subsequent application of 10 Hz stimulation ~40 min after Rp-cAMPs
washout produced LTP. C, Summary of experiments in which
10 Hz stimulation was applied in control slices (n = 5) or in slices bathed in Rp-cAMPs (n = 6).
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DISCUSSION |
The present experiments reveal that corticothalamic fibers
generate input-specific and reversible LTP in the ventrobasal thalamus. The results indicate that corticothalamic LTP is entirely presynaptic and appears to rely on the same mechanisms as LTP observed at hippocampal mossy fibers or cerebellar parallel fibers. The inability of glutamate receptor antagonists to impede the induction of
corticothalamic LTP strongly suggests that this form of LTP is
independent of postsynaptic depolarization or postsynaptic
Ca2+ influx. However, extracellular
Ca2+ is necessary for corticothalamic LTP,
suggesting that a rise in presynaptic Ca2+
is required. The results also show that LTP in corticothalamic fibers
is not dependent on NMDA receptor activation or disinhibition. This
reinforces the notion that postsynaptic mechanisms are not involved in
the induction of corticothalamic LTP. In pathways in which postsynaptic
depolarization and postsynaptic Ca2+ entry
are important (e.g., neocortex, Schaffer collaterals), LTP induction is
strongly facilitated by disinhibition and blocked by NMDA receptor
antagonists. The decrease in PPF during corticothalamic LTP provides
further evidence that not only the induction but also the expression of
this form of LTP is presynaptic and therefore caused by an
increase in neurotransmitter release. The results also show that
activation of adenylyl cyclase by forskolin causes a long-lasting
potentiation, which decreases PPF and occludes LTP induced by 10 Hz
stimulation. Moreover, application of a PKA inhibitor blocks the
generation of corticothalamic LTP. Together, the results can be
interpreted by a model put forward to explain LTP in hippocampal mossy
fibers (Huang et al., 1994; Weisskopf et al., 1994). In this model,
presynaptic Ca2+ entry activates an
adenylyl cyclase that, via cAMP and PKA, generates LTP through an
increase in neurotransmitter release probability.
Presynaptic PKA-dependent mechanisms involved in the generation of LTP
have been described in at least three different pathways: hippocampal
mossy fibers (Huang et al., 1994; Weisskopf et al., 1994), parallel
fibers (Salin et al., 1996), and lateral amygdala (Huang and
Kandel, 1998). In all of these pathways, LTP is expressed presynaptically. Our results reinforce the notion that PKA-dependent LTP is presynaptic. It is reasonable to assume that a
Ca2+-sensitive adenylyl cyclase should be
present in the neurons that express this form of LTP. Indeed, mRNA for
adenylyl cyclases are expressed at high levels in cerebellar granule
cells, hippocampal dentate granule cells, and neocortical cells from
which corticothalamic fibers originate (Glatt and Snyder, 1993).
Presynaptic PKA-dependent LTD has also been recently described in mossy
fibers (Kobayashi et al., 1996; Tzounopoulos et al., 1998). Further
work will need to determine whether corticothalamic LTD is also
mediated by similar mechanisms. Lack of postsynaptic involvement in LTP
was also evidenced by the fact that LTP was triggered in neurons that
did not produce either low-threshold calcium spikes or
orthodromic and antidromic action potentials with the synaptic
stimulation used. At the network level, activation of nRt neurons and
the release of GABA in the ventrobasal thalamus seem to be unnecessary
for LTP induction. This is suggested by the observation that glutamate
receptor antagonists, which block corticothalamic fiber collaterals in
nRt and thus GABA release, do not impede LTP induction.
The thalamus is the main relay station of information to the neocortex,
which then feeds back to the thalamus through corticothalamic fibers.
The existence of bi-directional long-term synaptic plasticity in this
massive corticothalamic feedback provides an activity-dependent mechanism to enhance or depress the efficacy of communication between
the neocortex and thalamus. Because the ventrobasal thalamus feeds back
to the neocortex, LTP and LTD would provide the means to change the
gain of information flow in the recurrent corticothalamic loop, thus
modifying cortico-cortical communication via the thalamus.
When do corticothalamic neurons discharge at 10 Hz (which produces LTP)
or at 1 Hz (which reverses LTP)? In whole animals, spindle oscillations
occur at 10 Hz during drowsiness and the early stages of sleep.
However, spindles are generated within the thalamus (for review, see
Steriade et al., 1993, 1997). Instead, during -rhythms, 10 Hz
activity is generated within the neocortex (Lopes da Silva et al.,
1980). These cortical rhythms at 10 Hz occur during awake immobility
just as an animal prepares for attentive processing but are abolished
immediately after the animal begins active exploration (Rougeul-Buser
and Buser, 1997). It is tempting to suggest that one of the functional
roles of these cortical preparatory rhythms is to enhance the
effectiveness of corticothalamic communication by potentiating
corticothalamic synapses. Interestingly, 1 Hz slow oscillations, which
would reverse LTP, are generated in the neocortex during slow-wave
sleep (Steriade et al., 1993). One of the functions for cortical slow
oscillations during sleep may be to reset (reduce) the efficacy of
corticothalamic synapses.
| |
FOOTNOTES |
Received May 20, 1999; revised July 1, 1999; accepted Aug. 2, 1999.
This work was supported by the Medical Research Council of Canada,
Fonds de la Recherche en Sante du Quebec, and the McGill University
Research Development Fund. We thank Drs. Robert Malenka and John Robson
for helpful comments on this manuscript.
Correspondence should be addressed to Dr. Manuel Castro-Alamancos,
Montreal Neurological Institute, 3801 University Street, Room WB210,
Montreal, Quebec H3A2B4, Canada.
| |
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TOP
ABSTRACT
INTRODUCTION
