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The Journal of Neuroscience, May 1, 2001, 21(9):2958-2966
Kainate Receptors Depress Excitatory Synaptic Transmission at
CA3 CA1 Synapses in the Hippocampus via a Direct Presynaptic
Action
Matthew
Frerking1,
Dietmar
Schmitz1,
Qiang
Zhou1,
Joshua
Johansen2, and
Roger A.
Nicoll1, 2
Departments of 1 Cellular and Molecular Pharmacology
and 2 Physiology, University of California, San Francisco,
California 94143-0450
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ABSTRACT |
Kainate receptor activation depresses synaptic release of
neurotransmitter at a number of synapses in the CNS. The mechanism underlying this depression is controversial, and both ionotropic and
metabotropic mechanisms have been suggested. We report here that the
AMPA/kainate receptor agonists domoate (DA) and kainate (KA) cause a
presynaptic depression of glutamatergic transmission at CA3 CA1
synapses in the hippocampus, which is not blocked by the AMPA receptor
antagonist GYKI 53655 but is blocked by the AMPA/KA receptor
antagonist CNQX. Neither a blockade of interneuronal discharge nor
antagonists of several neuromodulators affect the depression,
suggesting that it is not the result of indirect excitation and
subsequent release of a neuromodulator. Presynaptic depolarization, achieved via increasing extracellular K+, caused a
depression of the presynaptic fiber volley and an increase in the
frequency of miniature EPSCs. Neither effect was observed with DA,
suggesting that DA does not depress transmission via a presynaptic
depolarization. However, the effects of DA were abolished by the
G-protein inhibitors N-ethylmaleimide and pertussis toxin. These results suggest that KA receptor activation depresses synaptic transmission at this synapse via a direct, presynaptic, metabotropic action.
Key words:
domoate; kainate; metabotropic; presynaptic; hippocampus; CA1
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INTRODUCTION |
Neurotransmitter receptors in the
CNS can be separated into two broad classes: ionotropic
receptors, which are coupled to ligand-gated conductances, and
metabotropic receptors, which couple to GTP-binding proteins. Kainate
receptors (KARs) are ionotropic glutamate receptors that, in addition
to having conventional postsynaptic actions, are thought to act as
presynaptic inhibitors of transmitter release at a number of synapses
in the CNS (for review, see Frerking and Nicoll, 2000 ). The
mechanisms underlying this depression are controversial. Both direct
actions of presynaptic KARs (Chittajallu et al., 1996;
Rodríguez-Moreno et al., 1997; Schmitz et al., 2000) and
indirect actions of somatodendritic KARs (Frerking et al., 1999;
Chergui et al., 2000; Schmitz et al., 2000) have been proposed to
account for this presynaptic effect. The depression has also been
suggested to be the downstream result of presynaptic depolarization via
the conventional ionotropic actions of KARs (Chittajallu et al., 1996;
Kamiya and Ozawa, 1998; Schmitz et al., 2000) or alternatively
via a novel KAR-coupled metabotropic cascade
(Rodríguez-Moreno and Lerma, 1998; Rodríguez-Moreno et
al., 2000).
One difficulty in interpreting the effects of KAR activation is the
frequent presence of somatodendritic KARs on the presynaptic neurons,
which can lead to a number of different types of use-dependent depression. Glutamatergic CA3CA1 synapses in the hippocampus provide a good system in which to study the KAR-induced depression, because the somatodendritic region of the presynaptic CA3 cells can be
removed by microdissection. At these synapses, the KAR agonists kainate
(KA) and domoate (DA) both induce a depression of glutamate release
(Chittajallu et al., 1996; Kamiya and Ozawa, 1998; Vignes et al., 1998)
that is not accompanied by changes in presynaptic excitability, as
assessed by changes in the extracellular fiber volley (Kamiya and
Ozawa, 1998; Vignes et al., 1998), but is accompanied by a decrease in
presynaptic Ca2+ influx (Kamiya and Ozawa,
1998). However, these results do not exclude the possibility that the
KAR-induced depression is the indirect result of neuromodulators
released from CA1 interneurons, which fire intensely in response to KAR
activation (Cossart et al., 1998; Frerking et al., 1998), nor do they
address the relative contributions of ionotropic and metabotropic
mechanisms to the depression.
In this study, we examine the mechanism underlying the KAR-induced
presynaptic inhibition at glutamatergic CA3CA1 synapses in the
hippocampus. We confirm the previously described presynaptic actions of
DA. We find that the depressant action of DA cannot be explained by the
indirect release of a number of different neuromodulators and also
cannot be explained by an increase in interneuronal discharge,
suggesting that this presynaptic action is the direct result of KARs at
or near the presynaptic terminal. We find that the selective action of
DA on the field EPSP (fEPSP) is not mimicked by presynaptic
depolarization with extracellular K+,
which depresses the fEPSP and the fiber volley in parallel. However,
the effects of DA are abolished by the G-protein inhibitors N-ethylmaleimide (NEM) and pertussis toxin. These results
suggest that KARs depress release at this synapse via a direct,
metabotropic action.
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MATERIALS AND METHODS |
Slice preparation and recording techniques.
Hippocampal slices 300-400 µm thick were prepared from 2- to
12-week-old Sprague Dawley rats as described (Frerking et al., 1998).
After >1 hr of recovery time, a cut was made between area CA1 and area
CA2/CA3 to remove somatic effects of KA on CA3 pyramidal cells, and
slices were transferred to a submersion-type recording chamber perfused at room temperature with a solution consisting of (in mM):
119 NaCl, 26 NaHCO3, 10 glucose, 2.5 KCl, 4 CaCl2, 4 MgSO4, and 1.0 NaH2PO4, bubbled with 95%
O2-5% CO2. For whole-cell
recording, patch electrodes (2-5 M ) were filled with a solution
adjusted to pH 7.2, 270-290 mOsm, containing (in mM):
117.5 Cs gluconate, 10 tetraethylammonium chloride, 10 HEPES, 8 NaCl, 5 QX-314Cl, 4 MgATP, 2.5 CsCl, 0.3 Na3GTP, and 0.2 EGTA. Patch electrodes were filled with the external solution to
monitor extracellular field potentials. Field experiments were done
both in the presence and absence of 100 µM picrotoxin,
which had no effect on the depressant action of domoate (data not
shown). All whole-cell experiments on glutamatergic transmission were
done in the presence of 100 µM picrotoxin.
Stimulation and whole-cell recording techniques in slices were similar
to those described in Frerking et al. (1998). EPSCs were evoked every
15-20 sec and were filtered at 2 kHz and digitized at 5 kHz. Data were
analyzed on-line using Igor Pro (WaveMetrics, Inc., Lake Oswego, OR)
and off-line using Igor Pro and Sigma Plot (Jandel Scientific, San
Rafael, CA). K+-sensitive microelectrodes
were manufactured and tested as described previously (Lux and Neher,
1973; Heinemann et al., 1977).
Data analysis. All data are presented as the mean ± SEM. Significance was assessed at p < 0.05, using the
Student's t test and Pearson's product moment correlation.
EPSC amplitudes were calculated by subtracting a baseline period
preceding stimulation from a region of 2 msec during the peak of the
EPSC. 1/CV2, where CV is the coefficient
of variation, was calculated with noise subtraction.
Paired-pulse facilitation was measured as the ratio of amplitudes of a
second EPSC over the first, minus one, converted to a percentage.
Miniature EPSCs were detected using the Mini Analysis Program
(Synaptosoft, Inc., Leonia, NJ) and a detection threshold of 5-10 pA,
depending on the noise level. Field EPSP (fEPSP) slope measurements
were made using a time window of the initial 1-2 msec of the fEPSP,
set at the start of the experiment; fiber volley amplitude measurements
were made using the peak of the fiber volley. Experiments using
pharmacological manipulations that did not affect the DA-induced
depression were pooled together with control experiments and treated as
a single population where appropriate. The depolarization caused by
increasing extracellular K+ was estimated
using the Goldman-Hodgkin-Katz voltage equation, assuming that the
relative resting permeability of sodium in the bouton is ~1/20th that
of potassium and concentrations of K+ and
Na+ in the bouton are 120 and 10 mM, respectively.
Pertussis toxin injections. Pertussis toxin was injected
into the hippocampus of rats 2-3 d before slice preparation, as
described (Pitler and Alger, 1994). Briefly, rats were anesthetized
with sodium pentobarbital (50 mg/kg) and placed in a stereotaxic
apparatus. A small hole was drilled through the skull over the dorsal
right hippocampus, and three injections (1 µl each) of pertussis
toxin (1 µg/ml) were made at the coordinates relative to bregma
listed in Pitler and Alger (1994). The injections were made directly into the hippocampus, rather than into the ventricle, because this has
been reported to lead to more effective penetration of pertussis toxin
into the tissue without adverse side effects (Pitler and Alger, 1994).
The rats were then allowed to recover, and slices from the injected
hippocampus were made and used 2-3 d later. Only slices with track
marks from the injection needle were used, to ensure that the pertussis
toxin had been injected in the hippocampus near the site of recording.
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RESULTS |
Previous studies have reported that the AMPA/KA receptor agonist
DA, when applied at a low dose of 200 nM, specifically
activates kainate receptors (Bureau et al., 1999). We therefore
examined this dose of DA on the AMPA receptor (AMPAR)-mediated EPSC
recorded in CA1 pyramidal cells (Fig.
1A; n = 6) and the AMPAR-mediated fEPSP recorded extracellularly (see Fig.
2A; n = 8). The results from these two different measurements were
indistinguishable (p > 0.2) and when pooled
together gave an average depression of ~40% (Fig. 1C;
39 ± 5%; n = 14) for AMPAR-mediated
transmission, similar to that described by Kamiya and Ozawa (1998). To
confirm that this low dose of DA was not causing the depression via
activation of AMPARs, we examined the effects of DA on NMDA receptor
(NMDAR)-mediated EPSCs in the presence of the AMPAR-selective
antagonist GYKI 53655, at a concentration (10 µM) that blocks AMPAR function by > 90%, as assessed by blockade of the AMPAR-mediated fEPSP
(n = 4; data not shown), but is widely agreed to have
minimal effects on KARs (Paternain et al., 1995; Wilding and Huettner,
1995). DA under these conditions caused a depression of the
NMDAR-mediated EPSC (Fig. 1B-D; n = 4) that was indistinguishable from the effects on AMPAR-mediated
transmission in the absence of GYKI 53655 (p > 0.5), indicating that AMPARs are not involved in the depression induced
by DA. However, in the presence of the AMPA/KA receptor antagonist CNQX
(100 µM; n = 4), the effects of
DA on the NMDAR-mediated EPSC were abolished (Fig. 1C;
p < 0.02). The actions of DA were also not mediated
via activation of other glutamate receptors, because neither the NMDAR
antagonist APV (100 µM; n = 5)
nor a combination of the metabotropic glutamate receptor
antagonists methyl-4-carboxyphenylglycine (MCPG) and
cyclopropyl-4-phosphonophenylglycine (CPPG) (1.3 and 0.2 mM, respectively; n = 4) had any
effect on the depression (Fig. 1C).
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Figure 1.
KAR activation depresses glutamatergic
transmission at CA3CA1 synapses. A, Averaged,
stimulus-evoked AMPAR-mediated EPSCs are depressed by 200 nM DA. B, Averaged, stimulus-evoked
NMDAR-mediated EPSCs are depressed by 200 nM DA in the
presence of 10 µM GYKI 53655 (GYKI). C, The depressant action
of DA is not blocked by GYKI 53655, APV, or a combination of MCPG and
CPPG but is blocked by CNQX. Except for the data in GYKI 53655, which
examined NMDAR-mediated EPSCs, the results include data on
AMPAR-mediated EPSCs and fEPSPs that were pooled together.
D, The NMDAR-mediated EPSC amplitude
(filled circles) is compared with the input
resistance (open circles) as a function of time in the
presence of 10 µM GYKI 53655. Domoate application
is shown by the horizontal line. amp.,
Amplitude.
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Figure 2.
KAR activation reduces the probability of release.
A, Top, DA has a larger effect on the
first of two fEPSPs. Bottom traces show the paired-pulse
responses after scaling to the first fEPSP. B, A summary
of 23 experiments examining AMPAR-mediated transmission, pooled from
both field and whole-cell recordings, shows the change in paired-pulse
facilitation as a function of time. C, DA causes a
decrease in 1/CV2 of the EPSC that is correlated
with the decrease in mean EPSC amplitude. Individual experiments are
shown. D, DA has no effect on mEPSC amplitude.
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In previous studies, KAR activation has been reported to result in a
substantial decrease in the input resistance of CA1 pyramidal cells
(Frerking et al., 1999). However, the majority of this effect was
removed by the GABAA receptor antagonist
picrotoxin, which was present in all whole-cell recordings in the
present experiments. To examine more closely a possible role of changes
in the input resistance in the currently examined KAR-induced
depression, we compared the effects of DA on the input resistance and
the NMDAR-mediated EPSC recorded in the presence of GYKI 53655 (Fig.
1D). Under these experimental conditions, the holding
current changed by only 27 ± 16 pA, and there was no significant
reduction in the input resistance (Fig. 1D,
open circles) despite a robust decrease in the EPSC amplitude (Fig. 1D, filled circles). It
therefore seems unlikely that the KAR-induced depression of synaptic
transmission is mediated to any appreciable degree by changes in
passive membrane properties. DA also did not cause any change in the
frequency of spontaneous EPSCs (data not shown).
The KAR-induced depression has been reported to be presynaptic,
primarily because of associated changes in short-term plasticity (Kamiya and Ozawa, 1998; Vignes et al., 1998). We confirmed that DA
increases paired-pulse facilitation (Fig. 2A,B;
p < 0.01; n = 23), consistent with a
presynaptic locus of action. We also found that DA caused a substantial
reduction in the quantal content contributing to the AMPAR-mediated
EPSC, as assessed by changes in the 1/CV2
ratio of the EPSC (Fig. 2C; p < 0.01;
n = 6). To assess for possible postsynaptic effects, we
examined the effects of DA on the amplitude of miniature EPSCs
(mEPSCs); there was no change in the amplitude of mEPSCs after DA
application (Fig. 2D; n = 5; see
below). These results, collectively with the results in Figure 1
showing that the NMDAR and AMPAR components of the EPSC are depressed
to a similar extent and also showing that KAR activation does not cause a significant change in the input resistance under these conditions, provide strong evidence that the depressant effect of DA at this synapse is mainly, if not entirely, mediated via a presynaptic mechanism.
The results described thus far assess KAR activation via the use of the
agonist DA and address the potential activation of AMPARs via the use
of 10 µM GYKI 53655. To extend further the pharmacological correlation of the observed depression with the known
properties of KARs, we examined the effects of 10 µM KA on NMDAR-mediated EPSCs. Because of the lower specificity of KA for
KARs over AMPARs, we used a higher concentration of GYKI 53655 (100 µM) to remove completely the possibility of AMPAR
activation. Under these conditions, we found that KA caused a
substantial depression of the EPSC, similar in magnitude and time
course to that induced by DA (Fig.
3A,B, filled
circles; n = 10). This depression, as expected,
was blocked by CNQX (Fig. 3B, open circles;
n = 4). Also, consistent with results using DA, KA
caused a decrease in 1/CV2 (Fig.
3C; n = 10). The depression of the
NMDAR-mediated EPSC was also associated with changes in short-term
plasticity (data not shown). The similarity of the actions of KA and
DA, the sensitivity to CNQX, and the resistance to GYKI 53655 all
provide strong support for the idea that the agonist-induced depression
is mediated by KARs.
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Figure 3.
Kainate depresses the NMDA receptor-mediated EPSC.
A, Averaged, stimulus-evoked NMDA receptor-mediated
EPSCs are depressed by 10 µM KA in the presence of 100 µM GYKI 53655. B, The KA-induced
depression is shown as a function of time under control conditions
(filled circles) and in the presence of 100 µM CNQX (open circles). C,
KA causes a decrease in 1/CV2 of the EPSC that is
correlated with the decrease in mean EPSC amplitude. Individual
experiments are shown.
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Although the experiments performed so far indicate that the depression
ultimately is caused by presynaptic expression mechanisms, it is not
clear from these data whether or not the effects of KAR activation are
caused by the direct activation of presynaptic KARs on the terminal or
the indirect activation of somatodendritic KARs on some other cell
population in the slice preparation that then releases a neuromodulator
that acts heterosynaptically on the terminal. We therefore examined the
sensitivity of the DA-induced depression to antagonists for a number of
different neuromodulators known to affect synaptic transmission in area
CA1. We found that neither a combination of
8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and SCH 50911 (to block adenosine 1A and GABAB receptors,
respectively; n = 5) nor a combination of atropine,
1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190),
sulpiride, and N-nitro-arginine [to block muscarinic acetylcholine receptors, 5-HT1A receptors,
dopamine D2 receptors, and nitric oxide (NO) synthase,
respectively; n = 5] had any effect on the depression
of the fEPSP (Fig.
4A).
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Figure 4.
KAR activation does not depress transmission via
indirect interneuronal activation. A, A summary of
experiments shows that the normal effect of DA (mean ± SEM shown
as solid horizontal line ± dotted
horizontal lines) on fEPSPs is unaffected by both a cocktail of
antagonists for GABAB receptors (SCH 50911, 20 µM) and adenosine receptors (DPCPX, 10 µM)
and a cocktail of antagonists for muscarinic receptors (atropine, 10 µM), NO synthase
[N-nitro-L-arginine
(L-NNA), 100 µM], dopamine
receptors (sulpiride, 100 nM), and serotonin receptors
(NAN-190, 50 µM). B, Spontaneous IPSCs are
recorded at 0 mV. After addition of 200 nM DA, a large
increase in sIPSC frequency is observed. In a solution containing high
divalent concentrations (8 mM Ca and 17 mM Mg),
the DA-induced increase in sIPSC frequency is absent in a different
cell. C, The depressant action of DA on fEPSPs is
unaffected by the solution with high divalents. D, The
normal effect of DA on fEPSPs (filled circles) is
unaffected by the solution with high divalents (open
circles).
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Although the absence of any effect of these antagonists increases
confidence that the effect of DA on the fEPSP is direct, it remains
possible that DA activates a population of neurons to release some
neuromodulator that has not been blocked by these cocktails.
Hippocampal interneurons in particular are known to release a wide
variety of neuromodulatory substances upon activation and are also
known to be activated by somatodendritic KARs. This activation has been
reported to affect indirectly both inhibitory (Frerking et al., 1999)
and excitatory (Schmitz et al., 2000) transmission at other synapses in
the hippocampus. We therefore performed experiments to address more
generally the possibility that the effects of DA are indirectly
mediated by interneuronal activation. We found that, as expected if
KARs cause interneuronal discharge, DA dramatically increased the
spontaneous IPSC (sIPSC) frequency onto CA1 pyramidal cells (Fig.
4B; 1066 ± 228% of control values;
n = 4). It has been shown previously (Frerking et al., 1998) that KAR activation of interneuronal discharge can be prevented by a high divalent composition (8 mM
Ca2+ and 17 mM
Mg2+) of the extracellular solution
without altering the release probability, presumably by increasing the
charge screening. We confirmed that a solution containing 8 mM Ca2+ and 17 mM Mg2+ prevented
the DA-induced increase in interneuronal discharge, as assessed by the
increase in sIPSC frequency (Fig. 4B; 93 ± 13%
of control values; n = 4). However, the high-divalent
solution had no effect on the DA-induced depression of the fEPSP (Fig. 4C,D; n = 7), demonstrating that this effect
is not downstream of interneuronal discharge. We therefore conclude
that the depression is not mediated indirectly via the release of any
of the widely considered neuromodulators in the hippocampus and is
independent of interneuronal activity, suggesting a direct action of DA
on the presynaptic terminal.
Because KARs are ionotropic receptors and the effects of DA appear to
be direct, we wondered whether or not the DA-induced depression could
be explained by a presynaptic depolarization. One consequence of
presynaptic depolarization that has been widely suggested is that a
sufficiently large depolarization would inactivate sodium channels and
diminish spike amplitude; however, KAR activation has been reported to
depress transmission without affecting the presynaptic fiber volley,
which is an extracellular measurement of the compound action potential
(Kamiya and Ozawa, 1998; Vignes et al., 1998). One difficulty in
interpreting these results, however, is that under normal conditions
the fiber volley is much smaller than the fEPSP, making a comparison of
these parameters difficult in the same experiment. We therefore
examined the effects on the fiber volley and the fEPSP simultaneously
in the continued presence of 1-2 µM GYKI 53655, to
reduce the size of the fEPSP relative to that of the fiber volley.
Under these conditions, DA caused a depression of the fEPSP, whereas
the fiber volley was unaffected (Fig.
5A1,B,D;
n = 6). To test the relative sensitivities of the fiber
volley and the fEPSP, we then added tetrodotoxin to the solution, which
will depress Na channels in presynaptic axons and therefore also
transmitter release; we found that TTX caused a parallel reduction of
the fiber volley and the fEPSP (Fig.
5A2,B,D; n = 6),
confirming the sensitivity of the fiber volley under these conditions.
We then performed a similar comparison of the fiber volley and fEPSP
during stepwise increases in the extracellular K+ concentration, to depolarize the
presynaptic terminals. We found that, in contrast to DA, extracellular
K+ did not depress the fEPSP selectively;
concentrations of extracellular K+ that
depressed the fEPSP also depressed the fiber volley (Fig. 5C,D; n = 6). The observation that
extracellular K+ does not mimic DA
suggests that the DA-induced depression is not mediated by a
presynaptic depolarization.
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Figure 5.
KAR activation depresses synaptic transmission
without affecting fiber excitability. A, The fEPSP was
examined in the presence of submaximal concentrations of GYKI 53655 to
enhance resolution of the fiber volley.
A1, However, DA depressed the fEPSP
without affecting the fiber volley.
A2, In contrast, TTX depressed both
the fEPSP and the fiber volley. B, A summary of the
experiments in A is shown. The fEPSP (open
circles) was depressed by both DA and TTX, but the fiber volley
(filled circles) was affected only by TTX. Note
that the fiber volley and fEPSP are decreased by TTX in parallel,
suggesting that the depression of the fEPSP by TTX is the result of
decreased fiber excitability rather than synaptic inhibition. fEPSP
measurements shown after the break are renormalized to 100% at the
arrow to correct for a slight (~10%) overshoot in
recovery after DA application (data not shown). C, A
summary of experiments with elevated extracellular
K+ is shown. The fEPSP (open circles)
and fiber volley (filled circles) were similarly
depressed by slowly increasing the extracellular KCl concentration in
steps from 2.5 mM (control) to 5.5, 6.5, 7.5, 8.5, and
9.5 mM. The potentiation of the fEPSP after washout
was seen consistently but not studied further. D, A
summary of all experiments comparing the fEPSP and fiber volley is
shown. Black circles are experiments with DA,
white circles are experiments with TTX, and gray
circles are experiments with KCl. The dotted
lines represent selective effects on the synapse
(horizontal line) or on the fiber (diagonal
line). fv, Fiber volley.
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To perform a more general test for a DA-induced presynaptic
depolarization, we examined the effects of DA on mEPSC frequency. It is
well established that presynaptic depolarization increases mEPSC
frequency. The relationship between presynaptic depolarization and
spontaneous release is steep starting at approximately  50 mV
(Frerking et al., 1997); however, under normal conditions the presynaptic voltage is well below this threshold, and thus small depolarizations will have little effect on mEPSC frequency. We therefore examined mEPSCs in the presence of 15 mM
extracellular K+ to bring the presynaptic
voltage closer to this sensitive range of voltages. Under these
conditions, DA did not have any resolvable effect on mEPSC frequency
(Fig. 6A,C;
n = 5). To ensure that this assay is in fact sensitive
to small presynaptic depolarizations, an additional 5 mM K+ was applied,
which would be expected to cause a presynaptic depolarization of ~5
mV (see Materials and Methods). Unlike DA, this modest increase in
K+ caused a rapid and easily resolvable
increase in the frequency of mEPSCs (Fig. 6B,C;
n = 4). We conclude that DA under these conditions does
not resolvably depolarize the presynaptic terminal.
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Figure 6.
KAR activation by 200 nM DA does not
resolvably depolarize the presynaptic terminal. A,
mEPSCs are shown in control conditions, in which the concentration of
K+ has been increased to 15 mM to bring
the presynaptic membrane potential into a range in which small
depolarizations will cause an increase in Ca-dependent mEPSCs (see
text). DA has no effect on the mEPSC frequency. B,
Addition of 5 mM KCl, corresponding to an ~5 mV
depolarization, causes a pronounced increase in the frequency of mEPSCs
in a different cell. C, A summary of experiments
comparing the effects of DA (filled circles) and
5 mM KCl (open circles) on mEPSC frequency
is shown.
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If KARs are in fact present on the terminal, they should affect the
fiber volley with sufficient activation. We therefore examined the
fiber volley during application of 20 µM DA, in the presence of 100 µM GYKI 53655 to remove completely the
possibility of AMPA receptor activation at this high dose and also in
the presence of 100 µM cadmium to block calcium influx
and thereby prevent all depolarization-evoked transmitter or modulator
release. Under these conditions, DA causes a strong reduction of the
fiber volley (Fig. 7A,B;
n = 5). Although this effect could be attributable to a
direct depolarizing action of KARs on the presynaptic terminal, an
alternative is that somatodendritic KAR activation causes an increase
in K+ efflux that then causes the
depolarization. We therefore measured the extracellular
K+ levels in response to DA application
using K+-sensitive microelectrodes. The
K+ levels rose by ~4
mM in response to the DA application (Fig. 7C1; n = 4); however, bath
application of 4 mM KCl did not mimic the effects
of DA on the fiber volley (Fig. 7C2;
n = 5), indicating that the DA-induced increase in
extracellular K+ cannot explain the
DA-induced reduction of the fiber volley. These results indicate that
the presynaptic terminals do have kainate receptors, which with
sufficient activation cause substantial depolarization of the terminal;
however, lower doses of DA do not cause a resolvable depolarization but
nevertheless depress transmitter release.
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Figure 7.
Strong KAR activation depresses the fiber volley.
A, a, The fiber volley was recorded in the presence of
100 µM GYKI 53655 and 100 µM
CdCl2. b, After application of 20 µM DA, the fiber volley was substantially depressed.
c, The fiber volley recovered fully after washout.
B, A summary of the experiments in A is
shown. C1, The depression of the fiber
volley cannot be explained by K+ efflux. DA (20 µM) caused an increase in K+
levels of ~4 mM, as measured by
K+-sensitive microelectrodes.
C2, Application of 4 mM KCl under these conditions has no effect on the
fEPSP.
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If DA depresses transmitter release without causing a detectable
depolarization, what is the mechanism mediating this inhibitory action?
Rodríguez-Moreno and Lerma (1998) have suggested that presynaptic kainate receptors can depress transmitter release from
interneurons in the hippocampus via the depolarization-independent activation of a G-protein-coupled cascade. We therefore tested the
effects of the G-protein inhibitor NEM (200 µM) on the
DA-induced depression of the fEPSP. NEM has complex effects on baseline
synaptic transmission (Fig.
8A; n = 6), causing first an increase, probably because of inhibition of the
tonic depressant action of adenosine, and then a decrease, probably
because of a lower-affinity inhibition of the exocytotic protein
N-ethylmaleimide-sensitive factor, which is required
for transmitter release. Because of these complex effects, the effect
of NEM on the DA-induced depression of the fEPSP was assessed by
comparing the fEPSP as a function of time during DA application with
the fEPSP as a function of time during application of vehicle at the
same time window, after 15 min of NEM incubation (Fig.
8A, shaded box). During this time period, the fEPSP runs down by ~20% in NEM (Fig. 8B,C,
filled circles; n = 6). Application of DA
did not have any further effect on the fEPSP (Fig.
8B,C, open circles; n = 6), indicating that NEM prevents the effects of DA. To illustrate this
point more clearly, we corrected the fEPSP measurements in NEM during
the DA application by subtracting the effects of NEM alone during the
same time period (Fig. 8D, filled
circles). The corrected values show no effect of DA on the fEPSP
in NEM, and this is clearly different from the depressant action of DA
in the absence of NEM (Fig. 8D, open
circles).
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|
Figure 8.
NEM blocks the depressant action of 200 nM DA. A, After a control period
(a), NEM affects baseline synaptic transmission, causing
first an increase (b), and then a decrease (c).
During the time indicated by the shaded box, either DA
or vehicle was applied. B, fEPSPs run down during
the vehicle application as a function of time in NEM (top
traces), and no further effect is seen when DA is applied
instead of the vehicle solution (bottom traces).
C, A summary of experiments, in which the fEPSP slope is
normalized to that during the 5 min preceding application of DA or
vehicle. Experiments in which DA was applied (open
circles) are no different from those in which vehicle was
applied (filled circles). The total time window
in C corresponds to the region enclosed by
vertical dotted lines in A.
D, After removal of the baseline effects of NEM on
synaptic transmission by subtracting the depression caused by DA from
the depression caused by the vehicle, DA has no effect on the fEPSP in
NEM-treated slices (filled circles). For
comparison, the normal effect of DA in control conditions from Figure
4D is shown (open circles).
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|
To test further for the involvement of G-proteins, we examined the
effects of the G-protein inhibitor pertussis toxin on the DA-induced
depression of the fEPSP. Pertussis toxin, which selectively blocks
Gi/Go-mediated processes,
is reported to have very limited penetration in intact tissue, and
previous reports have indicated that injection of pertussis toxin
directly into the hippocampus 1-2 d before experiments is required to
obtain full effectiveness of this toxin in brain slices. We therefore
injected pertussis toxin into the hippocampus of 8- to 12-week-old rats
at three injection sites 2-3 d before experiments. We found,
consistent with the results using NEM, that DA had no effect on fEPSPs
in slices from pertussis toxin-injected rats (Fig.
9, filled circles; n = 7); in contrast, DA caused a robust depression in
age-matched controls (Fig. 9, open circles;
n = 6). We conclude that activation of an NEM- and
pertussis toxin-sensitive G-protein is required for the DA-induced
depression of glutamate release.
View larger version (16K):
[in this window]
[in a new window]
|
Figure 9.
Pertussis toxin blocks the depressant action of
200 nM DA. A, Averaged fEPSPs in slices from
pertussis toxin-injected rats (A1) and
age-matched controls (A2) are shown in
the presence and absence of DA. B, A summary of
experiments using slices from pertussis toxin-injected rats
(filled circles) and slices from age-matched
controls (open circles) is shown. PTX,
Pertussis toxin.
|
|
DA-induced G-protein activation could lead to a depression of synaptic
transmission via the well described, direct interaction between the
  G-protein subunits and calcium channels; alternatively, Rodríguez-Moreno and Lerma (1998) have suggested that a PKC
activation downstream of G-protein activity is essential for the
actions of KARs at inhibitory synapses. We therefore examined the
effects of preincubating the slices with the broad-spectrum
serine/threonine protein kinase inhibitor
1-(5-iso-quinolinesulfonyl)-2-methylpiperazine (H-7) and
found that it had no effect on the depressant action of DA [Fig.
10A,B; control slices
(n = 8), filled circles; treated slices
(n = 6), open circles]. To ensure that the
H-7 was effectively blocking protein kinase activity, we examined its
effects on the presynaptic potentiation induced by the adenylate
cyclase activator forskolin, coapplied with the phosphodiesterase
inhibitor IBMX (Chavez-Noriega and Stevens, 1994). As reported
previously, forskolin and IBMX caused a substantial potentiation of the
fEPSP under control conditions (Fig. 10C,D, filled
circles; n = 5); however, after preincubation with
H-7, this effect was strongly reduced (Fig. 10C,D,
open circles; n = 5), confirming the
effectiveness of H-7 in the present experiments. We conclude that
protein kinases do not appear to be required for the DA-induced
depression of glutamate release.
View larger version (29K):
[in this window]
[in a new window]
|
Figure 10.
Protein kinases are not involved in the
DA-induced depression of synaptic transmission. A,
Averaged fEPSPs are shown before and after application of 200 nM DA in control conditions (top traces) and
after incubation in the protein kinase inhibitor H-7 (bottom
traces). B, A summary of the experiments in
A is shown. The DA-induced depression in the presence of
H-7 (open circles) is not different from the depression
in control experiments (filled circles).
C, Averaged fEPSPs are shown before and after
application of forskolin and IBMX in control and H-7-treated slices.
Forskolin and IBMX together (each at 150 µM) cause a
potentiation of the fEPSP, which is strongly reduced in H-7-treated
slices. D, A summary of experiments shows that the
enhancement caused by forskolin and IBMX (filled
circles) is greatly reduced by H-7 (open
circles).
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| |
DISCUSSION |
We have performed experiments to elucidate the mechanism by which
KAR activation depresses excitatory synaptic transmission at CA3CA1
synapses in the hippocampus. It has been reported previously that KARs
cause a presynaptic depression of transmitter release, because KAR
activation depresses release from synaptosomes (Chittajallu et
al., 1996), acts on both the AMPAR- and NMDAR-mediated components of
the EPSC, alters short-term plasticity (Kamiya and Ozawa, 1998; Vignes
et al., 1998), and depresses presynaptic
Ca2+ influx (Kamiya and Ozawa, 1998). Our
results are entirely in agreement with this previous literature. We
have confirmed that KAR agonists can depress both components of the
EPSC and alter short-term plasticity, and we have also found that this
depression is associated with a reduction in quantal content, as
assessed by 1/CV2 measurements. The
absence of any KAR-induced change in input resistance, coupled with the
absence of any effect of KAR activation on mEPSC amplitude, suggests
that little, if any, of the depressant action of KARs on excitatory
transmission is postsynaptic.
The observation that KARs cause a presynaptic depression of synaptic
transmission does not necessarily indicate that KARs are located on the
presynaptic terminal; activation of KARs on other cells could cause the
release of a presynaptic neuromodulator that acts heterosynaptically.
This has in fact been a proposed mechanism of the KAR-induced
depressant action in a few systems (Frerking et al., 1999; Chergui et
al., 2000; Schmitz et al., 2000) (but see Rodríguez-Moreno et
al., 2000). Three broad lines of experimental evidence argue
against such a scenario in the present experiments. First, the
depression induced by DA is unaffected by antagonism of a number of
neuromodulators in the hippocampus. Second, the depression is
unaffected by increasing the divalent composition, a manipulation that
reduces cell excitability and prevents KAR-dependent interneuronal
spiking. Finally, strong KAR activation via a high dose of DA can
affect presynaptic fiber excitability even in the presence of cadmium
to block calcium influx-dependent neuromodulator release, providing
direct evidence of the existence of presynaptic KARs in this system.
These experiments strongly suggest that the KAR-induced depression of
glutamate release at CA3CA1 synapses is caused by the direct
activation of presynaptic KARs.
One possible indirect action of KARs that our experiments have not
addressed is the release of neuromodulators because of calcium influx
via calcium-permeable KARs, located either at the soma or on the
terminals of some other population of synapses. However, the
somatodendritic KARs on interneurons do not have the characteristically
nonlinear I-V relations of calcium-permeable KARs (Frerking
et al., 1998), making their involvement in such a cascade unlikely.
Moreover, if KARs on presynaptic terminals were calcium permeable,
their activation would lead to a large increase in the frequency of
miniature PSCs; such an increase has not been reported for mEPSCs (this
study) or miniature IPSCs (Rodríguez-Moreno et al., 1997;
Cossart et al., 1998; Frerking et al., 1998; Bureau et al., 1999) onto
CA1 pyramidal cells. We therefore think this scenario unlikely,
although we cannot exclude the possibility that some unidentified
population of cells that do not synapse onto CA1 pyramidal cells could
have these receptors and release a modulator that causes the effect.
Because of the evidence supporting a direct presynaptic action of KARs,
it is surprising that the effects of KAR activation, at least at low
doses, are distinct from those of presynaptic depolarization via
increasing extracellular K+. Although DA
depresses synaptic transmission without affecting the presynaptic fiber
volley, presynaptic depolarization affects both in parallel (see Fig.
5C). Moreover, even modest presynaptic depolarizations (~5
mV) cause a detectable change in mEPSC frequency in the presence of 15 mM extracellular K+,
but DA does not. However, a higher dose of DA robustly depresses the
fiber volley, suggesting that strong activation of KARs can depolarize
the terminal sufficiently to have presynaptic ionotropic effects. These
results indicate that low doses of DA that are sufficient to depress
synaptic transmission cause no detectable depolarization of the
presynaptic terminal and that the depression of release does not occur
via an ionotropic mechanism. Moreover, the observation that elevated
K+ depressed fiber excitability to the
same extent that it depressed transmission suggests that presynaptic
depolarization at this synapse has little direct effect on the synapse
but instead acts mainly by preventing spike initiation and/or
propagation. This would occur if axonal Na channels were inactivated at
more hyperpolarized potentials than were presynaptic Ca channels.
Strikingly, different results have been observed at mossy fiber
synapses in the hippocampus, where synaptic transmission is depressed
by levels of depolarization that enhance the fiber volley (Schmitz et
al., 2000).
The evidence that KARs do not depress release via ionotropic mechanisms
suggests that KARs activate a metabotropic signaling pathway, and the
observation that G-protein inhibitors block the KAR-dependent synaptic
depression is consistent with this suggestion. The sensitivity of the
KAR-induced depression to pertussis toxin implicates the
Gi/Go subtype of G-protein in
the effect. It is noteworthy that binding studies have suggested a
functional coupling between this subclass of G-protein and KARs in
hippocampal membranes (Cunha et al., 1999). AMPARs have also been
shown to couple to G-proteins (Wang et al., 1997; Kawai and Sterling,
1999). A major unresolved issue is how these receptors might activate
G-proteins, because they have little structural similarity to the
classical metabotropic receptors. A frequently proposed solution is
that an accessory protein acts as a link between G-proteins and KARs, but so far a protein with this role has not been identified. Another caveat concerning the involvement of G-proteins is that the
pharmacological blockade of the effect by G-protein inhibitors could
indicate that KARs activate a G-protein but could alternatively result from a nonspecific action of the inhibitors or a dependence of KAR
activity on G-proteins. Direct biochemical evidence will be required to
establish unequivocally KARs as activators of G-proteins and to
identify the protein-protein interactions that are involved.
We propose that presynaptic KARs couple to
Gi/Go G-proteins, which
causes the G-protein to dissociate into the  and / subunits. Because our results indicate that protein kinases are not required in
the signaling cascade, we suggest that the / subunits directly bind to and inhibit presynaptic Ca2+
channels and thereby depress release. This would be consistent with the
observation that KAR activation depresses stimulus-evoked presynaptic
Ca2+ transients at this synapse (Kamiya
and Ozawa, 1998). We further suggest that presynaptic KARs may be
sparsely distributed presynaptically, so that strong activation of KARs
is required to resolve the ionotropic activity of the KAR, but weak
activation appears to be sufficient to generate resolvable metabotropic
activity. This higher sensitivity of the metabotropic pathway is
presumably caused by the substantial biochemical amplification that
takes place at the level of receptor-G-protein coupling, although we
cannot at present exclude the alternative that separate, high-affinity
metabotropic and low-affinity ionotropic KARs are present.
The degree to which this model can be extrapolated to other systems is
unclear. KARs have been reported to activate a metabotropic cascade to
depress release at inhibitory synapses onto CA1 pyramidal cells
(Rodríguez-Moreno and Lerma, 1998; Cunha et al., 2000; Rodríguez-Moreno et al., 2000). However, because GABAergic
interneurons are strongly excited by KAR activation (Cossart et al.,
1998; Frerking et al., 1998; Bureau et al., 1999) and at least some of
the inhibition induced by KARs has been proposed to occur via the
indirect activation of metabotropic GABAB
receptors caused by that excitation (Frerking et al., 1998, 1999), to
what extent a direct presynaptic metabotropic action accounts for the
KA-induced depression at these synapses is controversial. KAR
activation is known to activate indirectly metabotropic cascades at
other synapses (Chergui et al., 2000; Schmitz et al., 2000).
Presynaptic KAR activation has also been reported to modulate
transmitter release via ionotropic mechanisms (Kamiya and Ozawa, 2000;
Schmitz et al., 2000). It therefore seems likely that KAR-dependent
modulation of transmitter release at different synapses operates via
different mechanisms.
In conclusion, we have provided evidence that presynaptic KARs depress
glutamate release at CA3CA1 synapses via a
depolarization-independent metabotropic cascade. The conditions under
which these receptors are activated and the role that they play remain
unclear. However, an autoreceptive function seems likely because of the
presynaptic location of these receptors at terminals releasing their
endogenous agonist. KARs are widely thought to play a role in
epileptiform activity, particularly in area CA3 of the hippocampus. The
depressant action of the presynaptic receptors described here will tend
to reduce transmission of epileptiform activity from CA3 to CA1, in
conjunction with the previously described "overinhibitory" action
of KARs on interneurons (Cossart et al., 1998). These results suggest
that KARs, depending on their location and mechanism of action, both
promote and reduce excitability in the hippocampus.
| |
FOOTNOTES |
Received Dec. 22, 2000; revised Feb. 5, 2001; accepted Feb. 7, 2001.
R.A.N. is a member of the Keck Center for Integrative Neuroscience and
the Silvio Conte Center for Neuroscience Research and is supported by
grants from the National Institutes of Health. D.S. is supported by a
grant from the Deutsche Forschungsgemeinschaft (Emmy-Noether-Programm).
We thank the members of the Nicoll laboratory for useful discussions.
Correspondence should be addressed to Dr. Roger A. Nicoll, Department
of Cellular and Molecular Pharmacology, University of California, San
Francisco, CA 94143-0450. E-mail: nicoll{at}phy.ucsf.edu.
| |
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The Role of the Hyperpolarization-Activated Cationic Current Ih in the Timing of Interictal Bursts in the Neonatal Hippocampus
J. Neurosci.,
May 1, 2003;
23(9):
3658 - 3668.
[Abstract]
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A. Contractor, A. W. Sailer, M. Darstein, C. Maron, J. Xu, G. T. Swanson, and S. F. Heinemann
Loss of Kainate Receptor-Mediated Heterosynaptic Facilitation of Mossy-Fiber Synapses in KA2-/- Mice
J. Neurosci.,
January 15, 2003;
23(2):
422 - 429.
[Abstract]
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M. F. M. Braga, V. Aroniadou-Anderjaska, J. Xie, and H. Li
Bidirectional Modulation of GABA Release by Presynaptic Glutamate Receptor 5 Kainate Receptors in the Basolateral Amygdala
J. Neurosci.,
January 15, 2003;
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442 - 452.
[Abstract]
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M. Frerking and P. Ohliger-Frerking
AMPA Receptors and Kainate Receptors Encode Different Features of Afferent Activity
J. Neurosci.,
September 1, 2002;
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[Abstract]
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T. L. Crowder and J. L. Weiner
Functional Characterization of Kainate Receptors in the Rat Nucleus Accumbens Core Region
J Neurophysiol,
July 1, 2002;
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41 - 48.
[Abstract]
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I. Khalilov, J. Hirsch, R. Cossart, and Y. Ben-Ari
Paradoxical Anti-Epileptic Effects of a GluR5 Agonist of Kainate Receptors
J Neurophysiol,
July 1, 2002;
88(1):
523 - 527.
[Abstract]
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L. Marshall, D. A. Henze, H. Hirase, X. Leinekugel, G. Dragoi, and G. Buzsaki
Hippocampal Pyramidal Cell-Interneuron Spike Transmission Is Frequency Dependent and Responsible for Place Modulation of Interneuron Discharge
J. Neurosci.,
January 15, 2002;
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[Abstract]
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TOP
ABSTRACT
INTRODUCTION
