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The Journal of Neuroscience, June 15, 2000, 20(12):4446-4451
Inhibition of the cAMP Pathway Decreases Early Long-Term
Potentiation at CA1 Hippocampal Synapses
Nonna A.
Otmakhova,
Nikolai
Otmakhov,
Lindsay H.
Mortenson, and
John E.
Lisman
Department of Biology and Volen Center for Complex Systems,
Brandeis University, Waltham, Massachusetts 02454
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ABSTRACT |
Long-term potentiation (LTP) has several different phases, and
there is general agreement that the late phase of LTP requires the
activation of adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). In contrast, several studies indicate that the early LTP
is not affected by interfering with the cAMP pathway. We have further
tested the role of the cAMP pathway in early LTP using several types of
inhibitors. Bath application of the PKA inhibitor H89 suppressed the
early LTP induced by a single tetanus. Similarly, the LTP induced by a
pairing protocol was decreased by postsynaptic intracellular perfusion
of the peptide PKA inhibitor PKI(6-22) amide. The decrease of LTP
produced by these inhibitors was evident immediately after induction.
These results indicate that PKA is important in early LTP, that its
locus of action is postsynaptic, and that it does not act merely by
enhancing the depolarization required for LTP induction. The
failure of some other inhibitors of the cAMP pathway to affect the
early phase of LTP might be attributable to the saturation of some step
in the cAMP pathway during a tetanus. In agreement with this hypothesis
we found that application of the AC inhibitor SQ 22536 by itself did
not affect the early phase of LTP, but did produce a reduction if the
cAMP pathway was already attenuated by the PKA inhibitor H89. Our
analysis of the results of genetic modifications of the cAMP pathway,
especially the work on AC knock-outs, indicates that the genetic data
are generally consistent with the pharmacological results showing the
importance of this pathway in early LTP.
Key words:
adenylyl cyclase; CA1; cAMP-dependent protein kinase; early LTP; H89; PKI(6-22) amide; SQ 22536
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INTRODUCTION |
Long-term potentiation (LTP) and
long-term depression (LTD) are activity-dependent modifications of
synaptic strength that are thought to underlie some forms of memory.
Both LTP and LTD induction requires the elevation of intracellular
Ca2+. This elevation, in turn, activates a
biochemical cascade that modifies synaptic strength. The intermediate
steps of this cascade are not well established. There is general
agreement that Ca2+-dependent protein
kinases and phosphatases are involved. Other second messenger pathways
have also been implicated, but their role is less clear (for review,
see Malenka and Nicoll, 1999 ).
In this paper, we focus on the role of the cAMP pathway in LTP at the
Schaffer collateral synapses on CA1 hippocampal pyramidal cells. It is
known that LTP induction produces a rise in cAMP (Chetkovich and
Sweatt, 1993), activation of PKA (Blitzer et al., 1995; Roberson and
Sweatt, 1996), and phosphorylation of some PKA substrates (Blitzer et
al., 1998), but the role of this pathway in LTP remains unclear despite
extensive genetic and pharmacological work. The issue is complex
because LTP is itself not a unitary phenomenon, but rather appears to
involve late, intermediate, and early phases (Frey et al., 1993; Huang
and Kandel, 1994; Winder et al., 1998) relevant to the mechanism of
memory consolidation (Bourtchouladze et al., 1998). Late LTP begins
~3 hr after induction, and there is general agreement that it depends
on cAMP and protein synthesis (Frey et al., 1993; Huang and Kandel,
1994; Winder et al., 1998), probably related to the formation of new
synapses (Bolshakov et al., 1997; Ma et al., 1999). It has been
reported that there is also an intermediate phase of LTP that begins
approximately an hour after induction and is dependent on cAMP, but not
protein synthesis (Winder et al., 1998).
The issue of whether early LTP depends on cAMP is less clear. The
standard measure of early LTP is the potentiation observed 30-40 min
after induction, a time at which short-term plasticity processes
induced by a tetanus have decayed. It is believed that early LTP does
not depend on AC or PKA (Frey et al., 1993; Huang and Kandel, 1994),
and there are several pharmacological and genetic studies that show
that interfering with the cAMP pathway does not affect early LTP (Qi et
al., 1996; Abel et al., 1997; Otmakhova and Lisman, 1998; Winder et
al., 1998). However, this conclusion cannot be considered definitive
because many of the genetic modifications did not lead to a substantial
change in measured enzyme activity, probably because of presence of
multiple enzyme isoforms and because the degree to which
pharmacological inhibitors actually inhibited the enzyme activity in
living cells could not be directly determined. We have reexamined the
role of the cAMP pathway using a broader range of inhibitors,
combinations of inhibitors, and more direct methods for introducing
inhibitors into the postsynaptic cell. The general conclusion we have
reached from our data and from reevaluation of the published genetic
evidence is that the cAMP pathway does have an important role in early LTP.
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MATERIALS AND METHODS |
Transverse hippocampal slices (350- to 400-µm-thick) were
prepared from 17- to 25-d-old Long-Evans rats. After preparation, slices were preincubated in an inverse interface chamber for 2-6 hr
before an experiment. The inverse interface conditions were created by
placing a slice in a drop of the artificial CSF (ACSF) on a
Millipore filter (pore diameter, 8 µm). The filters were held in the
humidified atmosphere of 95% O2 and 5%
CO2. In this condition the slice-gas interface
was at the bottom side of the slice rather then at the top side in the
standard interface chamber. In the experiment using field potential
recordings, slices were placed on a nylon net and perfused on both
sides with ACSF using a pump with flow rate 1.5-2.25 ml/min. ACSF
contained (in mM): NaCl 120, NaHCO4
26, NaH2PO4 1, KCl 2.5, MgSO4 1.3, CaCl2 2.5, and
D-glucose 10. Before entry into the recording chamber, ACSF was saturated with a gas mixture of 95% oxygen and 5% carbon dioxide and heated to the temperature 29-30oC.
When whole-cell patch-clamp experiments were performed, slices were
held submerged on the glass bottom of the recording chamber and were
continuously superfused (2 ml/min). Whole-cell recording was performed
at room temperature (~22-25oC). ACSF
was slightly modified: 4 mM CaCl2, 4 mM MgSO4. In addition, 50 µM picrotoxin was used to block
GABAA inhibition.
Field potential experiments. A glass recording
electrode filled with ACSF (resistance, 0.2-0.3 M ) was placed in
stratum radiatum of the CA1 region. To stimulate independent inputs,
two monopolar stimulating electrodes (glass pipettes filled with ACSF;
resistance, 0.25-0.35 M) were positioned on both sides of the
recording electrode ~200-250 µm apart from each other. Data were
acquired by personal computer with Digidata-1200 interface (Axon
Instruments, Foster City, CA) by a custom-made AXOBASIC program. The
strength of stimulation was adjusted so that field EPSP (fEPSP)
amplitude was 50% of the population spike threshold. The same stimulus
strength was used for both test and tetanic stimulation. The tetanus
used for the induction of early LTP consisted of 40 stimuli and lasted
0.6 sec (10 bursts of four stimuli at 100 Hz with 30 msec intervals between bursts). In some experiments three of such tetani 10 min apart
were given. Test stimulation alternated between two stimulating electrodes throughout the experiment at constant interval (10 sec). LTP
was induced after at least 15 min of a stable baseline and observed for
30-40 min after the induction. SQ 22536 (Research Biochemicals,
Natick, MA) was dissolved in ACSF and applied in the perfusion media
during the experiment. H89 (Calbiochem, La Jolla, CA) was dissolved in
DMSO (10 mM), diluted in regular ACSF to 20 µM, and used during preincubation of slices for 1-2 hr
before an experiment.
Whole-cell patch-clamp. Whole-cell recording was performed
using an Axopatch-1D amplifier (Axon Instruments) with low-pass filter
set at 1 kHz. The patch pipettes had a resistance of 2.5-3.5 M when
filled with pipette solution. The pipette solution contained (in
mM): Cs-methanesulfonate, 120; CsCl, 20; HEPES, 10; MgATP, 4; Na3GTP, 0.3; EGTA, 0.2; and phosphocreatine,
10; pH, 7.3; osmolarity, 300 mOsm. Patching was performed under visual
control using infrared oblique illumination and a CCD video camera.
Recordings were made from cell bodies in the CA1 pyramidal layer,
20-80 µm beneath the slice surface. Whole-cell currents were
measured in voltage-clamp mode at a holding potential of  65 mV.
Series and input resistances were monitored every 6 sec by measuring
the peak and steady-state currents in response to 2-4 mV, 38 msec
hyperpolarizing steps. Recorded signals were digitized at 5-10 kHz and
then stored and analyzed using custom software written in Axobasic
(Axon Instruments). Two stimulating electrodes (glass pipettes filled
with ACSF, 300 k) were placed in stratum radiatum to activate two
independent inputs of Schaffer collaterals. The electrodes were
positioned in the dendritic region at ~70 and 150 µm from the cell
body and ~50 µm lateral from the dendritic tree of the recorded
cell. Each input was stimulated every 6 sec with a 2-50 µA, 150 µsec square pulse delivered through current isolation units
(Isolator-11; Axon Instruments). The two inputs were stimulated
alternatively. LTP was induced using a pairing procedure in which a
cell was depolarized to 0 mV, and 200 stimuli were delivered to one of the inputs at 1.4 Hz.
Intracellular perfusion. Perfusion was performed as
described elsewhere (Otmakhov et al., 1997). This method allows
reliable intracellular introduction of substances without altering the electrophysiological characteristics of the recorded cell. Stock solutions of AC3 control peptide and PKI(6-22) amide (PKI), (20 mM both; QCB, Hopkinton, MA) were prepared in deionized
water and stored in aliquots at 70°C. AC3 control peptide has a
reversed sequence relative to AC3 inhibitory peptide of
Ca2+-calmodulin-dependent protein kinase 2 (CaMKII) (Otmakhov et al., 1997). On the day of an experiment a fresh
aliquot was diluted in standard internal solution concentrated by 10%,
and the osmolarity was adjusted to 300 mOsm. All peptides were applied
in 2 mM concentrations. At similar concentration (1 mM) peptide inhibitors were shown to block the
PKA-dependent inhibition of afterhyperpolarization (AHP) (Pedarzani and
Storm, 1993, 1996). The AHP is though to be generated closer to the
cell body (Sah and Bekkers, 1996) than the synaptic processes we have
studied. We could not allow a long time for diffusion of peptide in
dendrites because of the possibility of "washout" of LTP. Direct
measurements of diffusion of dye in the dendrites show that the
equilibration takes ~40 min (Otmakhov et al., 1997). The dye used,
however, had a much lower molecular weight as compared to peptides we
use in these experiments. The intracellular concentration of peptides
can also be decreased by a proteolysis (Otmakhov et al., 1997). Thus,
the actual concentration of peptide at synapses at the time of LTP
induction (only 12 min of perfusion) would be much lower than that in
the pipette solution.
Statistical analysis. For statistical analysis of fEPSP
experiments responses were first collected and averaged in 5 min
blocks: 15 min of baseline and 40 min after the tetanus. Field EPSP
slope (millivolts per millisecond) and fiber volley amplitude
(millivolts) were calculated, and data for each experiment were
normalized relative to baseline. The amplitude of a synaptic response
in whole-cell voltage clamp experiments was calculated by subtracting the average value of the data points in a 15 msec window before the
stimulus from the average value of the data points in a 3 msec window
at the peak of the synaptic response. In figures, the amplitude
measurements from individual experiments were first averaged over 1 min
periods, then normalized to the baseline period before pairing, and
finally averaged across experiments. Two way ANOVA for repeated
measurements (df = 1 for drug and df = 5 for time after the
tetanus factors) and a two-tailed t test for means as a
post hoc criterion in the Excel program package with
 < 0.05 were used as criteria for significance. When results
from different slices (or cells) were compared, we performed a one-way ANOVA or multiple two-tailed unpaired t tests at the same
time intervals. For graphic presentations, data were collected and averaged in 1 min blocks. Figures show means ± SEs.
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RESULTS |
We first performed experiments using a PKA inhibitor, H89 (Chijiwa
et al., 1990). Slices were pretreated (1-2 hr) with the drug, as
previously described (Thomas et al., 1996; Otmakhova and Lisman, 1998).
Each day 3 slices from the same animal were used. One slice was used as
a control, one was presoaked for 2 hr in 20 µM H89
(dissolved in 0.2% DMSO), and one was presoaked for the same time in
the vehicle (0.2% DMSO in ACSF). Slices were then transferred to the
experimental chamber and perfused with ACSF. To induce LTP, slices were
stimulated with a single tetanus. As shown in Figure
1, at all times after induction, LTP was
smaller in H89 than in vehicle-treated or control slices
(p < 0.05; n = 7). At the 30 min point, LTP was decreased by 52% relative to DMSO
(p < 0.02).
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Figure 1.
The PKA inhibitor H89 suppressed the early LTP
induced by a single tetanus. In slices pretreated with H89 (20 µM), early LTP was strongly reduced as compared to both
control and vehicle groups (p < 0.05;
n = 7 for each group). There was no difference
between control and vehicle (0.2% DMSO)-treated slices.
Insets represent averaged (n = 6)
fEPSP from individual experiments before and 30 min after the tetanus.
Field EPSP slopes were normalized relative to the baseline. The figure
shows means and SE. The arrow indicates the time of the
tetanus.
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The action of H89 is unlikely to be a secondary effect of changes in
excitability because, by several measures, excitability was unaffected.
The standard stimulus was adjusted in all three groups to evoke a fEPSP
slope half that required to elicit a population spike. This slope, the
amplitude of the fEPSP, and the amplitude of the fiber volley before
the tetanus were all statistically indistinguishable
(p > 0.5; p > 0.5; and
p > 0.3 in a one-way ANOVA) between control, DMSO, and
H89 groups. Field EPSP maximal slopes were 0.58 ± 0.03, 0.59 ± 0.03, and 0.54 ± 0.04 mV/msec; fEPSP amplitudes were 0.87 ± 0.08, 0.78 ± 0.12, and 0.94 ± 0.07 mV; fiber volleys
were 0.34 ± 0.04, 0.34 ± 0.03, and 0.28 ± 0.025 mV,
respectively. We also did not see any differences in field potential
dynamics during the tetanus. The degree of fEPSP suppression (last
relative to first fEPSP in the train) during tetanus were similar in
all three groups (p > 0.6). Population spike
was rarely observed during the tetanus, and the incidence of population
spikes did not differ between control, DMSO, and H89 groups
(p > 0.5 in a one-way ANOVA).
To study the involvement of PKA in early LTP by a second, independent
method, we applied the PKA inhibitor PKI into the postsynaptic cell
through the patch pipette. This inhibitor is a membrane-impermeable peptide, so any effect of postsynaptic application can be specifically attributed to postsynaptic targets. LTP was induced by a pairing procedure that combined synaptic stimulation (1.4 Hz, 200 stimuli) with
simultaneous depolarization of the postsynaptic cell to 0 mV. We
induced LTP by pairing in one of two inputs 6 min after the initiation
of whole-cell recording (baseline) (Fig.
2A). Two minutes after
this pairing, PKI (2 mM) was perfused into the
cell so that its effect on subsequent LTP induction (12 min later) in a
second input could be determined. In the presence of PKI (Fig.
2A), LTP was significantly smaller than without PKI
(by 30% on average: ANOVA, F = 190.5;
p < 0.001; n = 8). In control experiments we tested the effects of a different peptide that does not
have a PKA-specific action, the AC3 peptide. Under the same
experimental conditions, the AC3 peptide did not affect pairing-induced LTP (Fig. 2B; ANOVA, F = 0.85;
p > 0.35; n = 6). In both experiments holding current, series, and input resistances were stable at the 65
mV membrane potential at which the EPSC were recorded. Figure
2C shows that the LTP induced in the presence of PKI was smaller (by 32% at 30 min after pairing; p < 0.01;
t test) than in the presence of control peptide.
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Figure 2.
Intracellular perfusion of the PKA inhibitor
PKI(6-22) amide (2 mM) decreased the early LTP induced by
pairing. A, In the first input, pairing procedure
induced large LTP. Two minutes after pairing, PKI was perfused inside
the cell. A pairing procedure applied to the second input in the
presence of PKI produced significantly smaller LTP
(n = 8; p < 0.001).
B, In similar experiments, AC3 control peptide (2 mM) was perfused into the cell after the first pairing. A
pairing procedure applied to the second input (in the presence of AC3)
produced LTP of the same size as a first pairing (n = 6; p > 0.35). C, Replot of LTP
induced by second pairing procedure shows significant inhibition of LTP
by PKI as compared to control peptide (p < 0.01). Insets represent averaged EPSC
(n = 40) from individual experiments 5 min before
and 30 min after the pairing.
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We next sought to understand why we and others failed to detect changes
in LTP produced by other inhibitors of the cAMP/PKA pathway. In initial
experiments, we checked whether we could repeat our previous finding
(Otmakhova and Lisman, 1998) that bath application of the AC inhibitor,
SQ 22536, did not affect early LTP. A concentration of 100 µM was used because previous work showed that this
concentration inhibited the AHP that follows a train of action
potentials (Madison and Nicoll, 1986) and facilitated depotentiation
(Otmakhova and Lisman, 1998). Application of SQ 22536 produced a small,
reversible increase in the baseline responses (6.8 ± 1.2%;
p < 0.01; two-tailed paired t test). In
each slice LTP was induced by a single tetanus in one input under
control conditions, in the second input after 10-20 min of application
of SQ 22536. As shown in Figure
3A, SQ 22536 did not
significantly affect early LTP (ANOVA; F = 1.104; p > 0.3; n = 7), consistent with our
previous results (Otmakhova and Lisman, 1998).
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Figure 3.
Inhibition of AC significantly decreased early LTP
when combined with the inhibition of PKA. A, The AC
inhibitor SQ 22536 (100 µM) alone did not affect early
LTP induced by a single tetanus (n = 7;
p > 0.3). B, In slices pretreated
with the PKA inhibitor H89 (2 hr, 20 µM), application of
the AC inhibitor SQ 22536 (100 µM) significantly
decreased the early LTP induced by a single tetanus
(n = 7; p < 0.001).
Insets represent averaged (n = 6)
fEPSP from individual experiments taken at 5 min before and 30 min
after the tetanus. All calculations and markings are as in Figure 1.
Note that LTP after the application of H89 in B is
larger than the H89 condition in Figure 1. This difference should not
be considered significant because the experiments were done at
different times, and variability in LTP magnitude is common.
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One possible explanation of the lack of effect of SQ 22536 may be that
the inhibition of AC is only partial and that the remaining elevation
of cAMP during a tetanus is still sufficient to fully perform the
downstream functions required for LTP induction (i.e., the downstream
pathway is normally saturated). If this is the case, an effect of SQ
22536 should become apparent if the pathway is already attenuated by
some other inhibitor, thus removing the pathway from saturation. We
therefore studied the effect of SQ 22536 under conditions where the
slice was pre-exposed to 20 µM H89 (2 hr). In one of the
inputs, LTP was induced by a single tetanus without additional drug
application (Fig. 3B, H89); in the other input LTP was
induced by a single tetanus after the application of 100 µM SQ 22536 (Fig. 3B, H89 + SQ
22536). The results show that under these conditions, SQ 22536 produced
a substantial additional decrease of early LTP (ANOVA,
F = 12.038; p < 0.001;
n = 7). This decrease was statistically significant (p < 0.05 in post hoc paired
t test) in all but the first 5 min time interval after the
tetanus. At 30 min, SQ 22536 decreased LTP by 40% relative to H89
alone (p < 0.01). Thus when the AC/PKA pathway
is already partially inhibited, further inhibition by SQ 22536 produces
a large reduction of early LTP.
Because of data indicating that agents that inhibit PKA decrease the
LTP induced by three tetani more strongly than that induced by a single
tetanus (Huang and Kandel, 1994), it was of interest to determine
whether this was also the case for an AC inhibitor. In these
experiments, LTP was produced by three tetani given 10 min apart. SQ
22536 (100 µM) was applied from 20 min before the first
tetanus until the end of the third tetanus. Control and drug conditions
were measured sequentially in two pathways in the same slice. As in
other studies (Huang and Kandel, 1994; Winder et al., 1998), under
control conditions, three tetani produced LTP that was almost twice as
large as that produced by a single tetanus (p < 0.05; n = 7 in each group). As shown in Figure
4, SQ 22536 alone significantly inhibited
three tetani LTP (27% on average; ANOVA, F = 19.4;
p < 0.001; n = 7).
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Figure 4.
The AC inhibitor SQ 22536 inhibited early LTP
induced by three tetani. The LTP induced by three tetani was
significantly larger than the LTP induced by a single tetanus
(p < 0.05). AC inhibitor SQ 22536 (100 µM) inhibited the early LTP induced by three tetani
(p < 0.001; n = 7).
Insets represent averaged (n = 6)
fEPSP from individual experiments taken at 5 min before and 30 min
after the tetanus. All calculations and markings are as in Figure 1.
Field EPSP between tetani are not shown.
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DISCUSSION |
The results presented here demonstrate that three different
pharmacological agents (H89, PKI, and SQ 22536) that inhibit the AC/PKA
pathway produce a substantial decrease of the early phase of LTP. The
inhibitors we have used have different targets and were applied in
different ways, allowing us to make several points about the
involvement of this pathway. We found that bath application of H89
produced a ~50% inhibition of the early LTP induced by a single
tetanus. This inhibition was apparent immediately after induction and
was maintained for as long as we monitored the slice. We also applied
the membrane-impermeable PKA inhibitor PKI directly to the postsynaptic
neuron. This produced a ~30% decrease in LTP. These experiments thus
indicate that a locus of PKA action on early LTP is postsynaptic (see
also Blitzer et al., 1995). Because a pairing procedure was used in
these latter experiments, the results indicate that the AC/PKA pathway
is directly involved in the biochemical machinery of synaptic
modification rather than in generating the depolarization required for
LTP induction. As has been noted (Sanes and Lichtman, 1999), a general
weakness of experiments that use LTP induction by tetanic stimulation
is that the number of factors that can influence induction is very large, including the action of interneurons, frequency-dependent presynaptic properties, and postsynaptic conductances. In contrast, when LTP is induced by pairing, these complexities do not come into
play because inhibition is blocked by picrotoxin, depolarization is
imposed by clamp, and only low-frequency stimulation is used.
It is not yet possible to say whether LTP can be only partially
inhibited by interfering with the cAMP pathway or whether it can be
totally inhibited. It was shown before (Blitzer et al., 1995) that the
early LTP induced by three tetani can be almost completely blocked by
the PKA inhibitor Rp-cAMPS. Similarly in a separate study (Otmakhov et
al., 1999), we have found that postsynaptic application of Rp-cAMPS (4 mM) completely blocked the LTP induced by pairing. However,
our results (Otmakhov et al., 1999) suggest that Rp-cAMPS might act on
some other target in addition to PKA. Thus, based on the current
evidence, all that can be said is that inhibition of PKA produces at
least a 30-50% reduction of LTP.
Our results provide new insight into why some manipulations of the cAMP
pathway might not affect early LTP. We have replicated our previous
results (Otmakhova and Lisman, 1998) that early LTP was not affected by
the adenylyl cyclase inhibitor SQ 22536. However, we now find that when
SQ 22536 is applied under conditions when the AC/PKA pathway has been
already attenuated by H89, SQ 22536 produce a large additional decrease
of LTP. This suggests that the failure of SQ 22536 to be effective by
itself might be attributable to a saturation effect; the elevation of
cAMP during a tetanus may be so large that it saturates downstream
processes. In this case, partial inhibition of AC may have little
effect. However, if the downstream processes are brought out of
saturation by PKA inhibitor, the effect of AC inhibitor can be
revealed. The lack of effectiveness of PKA inhibitor KT 5720 on
1-tetanus LTP (Huang and Kandel, 1994) might have a similar
explanation. The possibility of such saturation may seem to contradict
the fact that LTP can be enhanced by agents that increase cAMP
(Otmakhova and Lisman, 1996, 1998; Barad et al., 1998), however these
agents are not strictly comparable. Specifically, agents that inhibit
the pathway will primarily decrease the amplitude of the activation,
whereas agents that increase the cAMP concentration also prolong its
period of action (some agents such as forskolin produce a tonic
elevation of cAMP; other agents, such as the phosphodiesterase
inhibitor rolipram presumably prolong the tetanically induced elevation).
Several different enzymes that affect the cAMP/PKA pathway have been
altered genetically, and it is important to assess whether the
conclusion derived from these studies are in agreement or disagreement
with the conclusion we have derived from pharmacological studies. The
strongest evidence for involvement of the cAMP pathway in early LTP has
come from work on adenylyl cyclase knock-outs. Initial work with a
knockout of the Ca2+-activated AC1 (Wu et
al., 1995), showed that late LTP was unaffected while early LTP was
slightly decreased. However, biochemical experiments showed only a
modest (46%) decrease in Ca2+-dependent
cyclase activity in the hippocampus. The reason for relatively small
biochemical effect was recently demonstrated in experiments in which
the two major Ca2+-dependent adenylyl
cyclases (AC1 and AC8) were knocked out (Wong et al., 1999). In this
case, Ca2+-dependent cyclase activity in
the hippocampus was completely abolished. The focus of this study was
on late LTP, so the authors did not explicitly discuss their findings
on early LTP. However, their results (Wong et al., 1999, their Fig.
3D) clearly show that early LTP was dramatically decreased
(by ~ 35% at 30 min). These results thus strongly support the
involvement of AC in early LTP.
Several genetic perturbations of PKA have also been made, but no
knock-out has yet been found that strongly affects the total PKA
activity. The knock-out of regulatory subunit R1 beta
(Brandon et al., 1995) did not produce measurable changes in total PKA activity and did not show any effect on early or late LTP. This might
be because it is the R2 type of regulatory subunit, anchored by AKAP-79
to the PSD (Carr et al., 1992), which is the form important for
synaptic function (Rosenmund et al., 1994). In other experiments involving knock-out of C beta1 catalytic subunits (Qi et
al., 1996) there was no measurable change in total PKA activity, but there was modest (~20%) decrease of the early LTP induced by three tetani (Qi et al., 1996, their Fig. 2B). In yet
another study, total PKA activity was reduced 20-30% by expression of
the R(AB) inhibitory form of regulatory subunit (Abel et
al., 1997). This produced a substantial reduction (30-50%) of the
early LTP induced by three tetani (Abel et al., 1997, their Fig.
4C). We conclude that the genetic work with PKA provides
some support for a role of PKA in early LTP and is certainly not
inconsistent with such a role.
An important question that remains to be investigated is why agents
that interfere with the cAMP pathway have a greater effect on the LTP
induced by three tetani than that induced by a single tetanus (Huang
and Kandel, 1994; Abel et al., 1997). This pattern of effects has been
recently reported for early LTP (Blitzer et al., 1995) using Rp-cAMPS,
and we have replicated this finding with SQ 22536. Our results thus in
no way contradict the idea that PKA may participate in multiple
processes, some of which might be only involved in late LTP. Indeed it
would seem quite likely that an initial period of activity would
produce changes in the cell that could affect subsequent
activity-dependent plasticity. This phenomenon has been termed
metaplasticity (Abraham and Bear, 1996).
It will be of interest to determine what reactions are involved in the
regulation of early LTP by PKA. One possibility is suggested by recent
work showing that PKA is closely linked to the NMDA channel by the
synaptic scaffolding protein yotiao (Westphal et al., 1999). These
results raise the possibility that inhibition of PKA reduces the NMDA
conductance and thereby decreases LTP. Alternatively, disinhibition of
protein phosphatase 1 by PKA inhibitors may decrease the
autophosphorylation of CaMKII which is required for the induction of
LTP (Lisman, 1994; Coussens and Teyler, 1996; Blitzer et al., 1998).
Further experiments will be required to distinguish between these and
other possible models of PKA involvement in early LTP.
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FOOTNOTES |
Received Feb. 18, 2000; revised March 28, 2000; accepted March 30, 2000.
This work was supported by National Institutes of Health Grants 2R01
NS27337/11 and 1R01 NS35083/03 and Alzheimer Association Grants
RG3-96-015 to J.L., and National Institutes of Health Grant 5F32
MH11720-02, National Alliance for Research on Schizophrenia and
Depression Young Investigator Award, and the Scottish Rite Schizophrenia Research Program, NMJ grants to N.O. Howard Hughes Undergraduate Initiative 71199-513104 00 supported work of L.M. We also
appreciate the support from W. M. Keck Foundation.
Correspondence should be addressed to John E. Lisman, Biology
Department, Center for Complex Systems, Brandeis University, 415 South Street, Waltham, MA 02454. E-mail: Lisman{at}binah.cc.brandeis.edu.
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TOP
ABSTRACT
INTRODUCTION
