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The Journal of Neuroscience, April 15, 1999, 19(8):2954-2959
AMPA Receptor Activates a G-Protein that Suppresses a
cGMP-Gated Current
Fusao
Kawai1, 2 and
Peter
Sterling1
1 Department of Neuroscience, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6058, and
2 Department of Information Physiology, National Institute
for Physiological Sciences, Okazaki 444, Japan
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ABSTRACT |
The AMPA receptor, ubiquitous in brain, is termed "ionotropic"
because it gates an ion channel directly. We found that an AMPA
receptor can also modulate a G-protein to gate an ion channel indirectly. Glutamate applied to a retinal ganglion cell briefly suppresses the inward current through a cGMP-gated channel. AMPA and
kainate also suppress the current, an effect that is blocked both by
their general antagonist CNQX and also by the relatively specific AMPA
receptor antagonist GYKI-52466. Neither NMDA nor agonists of
metabotropic glutamate receptors are effective. The AMPA-induced
suppression of the cGMP-gated current is blocked when the patch pipette
includes GDP- -S, whereas the suppression is irreversible when the
pipette contains GTP- -S. This suggests a G-protein mediator, and,
consistent with this, pertussis toxin blocks the current suppression.
Nitric oxide (NO) donors induce the current suppressed by AMPA, and
phosphodiesterase inhibitors prevent the suppression. Apparently, the
AMPA receptor can exhibit a "metabotropic" activity that
allows it to antagonize excitation evoked by NO.
Key words:
AMPA; glutamate; ionotropic; metabotropic; G-protein; retina; rat
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INTRODUCTION |
Glutamate, the major excitatory
transmitter in brain, activates a class of receptors termed
"ionotropic" because they directly gate ion channels (Nakanishi,
1992 ; Seeburg, 1993; Hille, 1994; Riedel, 1996; Pass, 1998). Recently,
an ionotropic glutamate receptor of the subclass that binds AMPA
was discovered in cortical homogenates to also have a
"metabotropic" function: it activates a G-protein to suppress
adenylyl cyclase (Wang et al., 1997). We wondered whether the AMPA
receptor has other metabotropic functions and whether these might
include indirect gating of ion channels. We thought to probe for a
metabotropic effect in a system suited for subsequent investigation of
its role in neural integration.
We chose the retinal ganglion cell because the effects of stimulating
its dendritic AMPA receptors can be investigated in a slice preparation
(Aizenman et al., 1988; Mittman et al., 1990; Cohen et al., 1994;
Leinders-Zufall et al., 1994; Taylor et al., 1995; Zhang et al., 1995;
Coleman and Miller, 1998; Matsui et al., 1998) and because the role in
neural integration could then be investigated in the intact retina
in vitro. Certain ganglion cells express a cGMP-gated
channel that causes an inward current when nitric oxide (NO) stimulates
guanylyl cyclase to raise [cGMP] (Ahmad et al., 1994). The natural
source of NO is probably a class of amacrine cell that stains intensely
for NADPH diaphorase (NO synthase) (Sandell, 1985; Sager, 1986).
Reasoning that a current stimulated by one signal (NO) ought to be
antagonized by another, we tested the AMPA receptor and discovered that
in retinal ganglion cells it can activate a G-protein to suppress the
cGMP-gated current.
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MATERIALS AND METHODS |
Preparation and recording. Slices from adult rat
retina were cut at 200 µm (Werblin, 1978) and viewed on a Zeiss
(Oberkochen, Germany) upright microscope with differential
interference contrast optics (×40 water-immersion objective). Ganglion
cells were identified in the slice by their position and size. Membrane
currents were recorded in the whole-cell configuration (Hamill et al.,
1981) using a patch-clamp amplifier (Axopatch 200A; Axon Instruments, Foster City, CA) linked to a computer. The voltage-clamp procedures were controlled by the pClamp software (Axon Instruments). Data were
low-pass filtered (four-pole Bessel type) with a cutoff frequency of 5 kHz and then digitized at 10 kHz by an analog-to-digital interface. All
experiments were performed at room temperature (23-25°C).
Solutions and drugs. The control Ringer's solution
contained (in mM): NaCl, 135; KCl, 5;
CaCl2, 1; MgCl2, 1; HEPES, 10;
and glucose, 10. The solution was adjusted with NaOH to pH 7.4 and bubbled with oxygen. CoCl2 (1 mM), picrotoxin
(100 µM), and strychnine (1 µM) were also
added to block synaptic transmission. The recording pipette contained
(in mM): CsCl, 140; CaCl2, 1; EGTA or
BAPTA, 5; HEPES, 10; and Mg-ATP, 2. The solution was adjusted with CsOH to pH 7.4. Pipette resistance was ~7 M .
Test substances were applied through the bath
[8-bromo-cGMP, 8-bromo-cAMP, 8-p-chlorophenylthio-cGMP,
CNQX, GYKI-52466,  -methyl-4-caboxyphenylglycine (MCPG),
-cyclopropyl-4-phosphonophenylglycine (CPPG),
1-methyl-3-isobutylxanthine (IBMX), zaprinast, methylene blue,
or sodium nitroprusside], via pressure ejection for 1 sec from a
"puffer" pipette (glutamate, AMPA, kainate, NMDA,
L-2-amino-4-phosphonobutyrate [L-AP-4], or 1S,3R-1-aminocyclopentane-trans-1,3-dicarboxylic
acid [trans-(1S,3R)-ACPD]), or via
the patch pipette (cGMP, GTP--S, GDP--S, pertussis toxin, or
cholera toxin). MCPG and CPPG were purchased from Tocris Cookson (Ballwin, MO). Other chemicals were from Sigma (St. Louis, MO).
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RESULTS |
Recording from ganglion cells in the slice preparation of adult
rat retina, we confirmed the observations of Ahmad et al. (1994) that
certain ganglion cells express a cGMP-gated current. When a
membrane-permeant analog of cGMP (8-bromo-cGMP) was bath-applied at 1 mM to a ganglion cell voltage-clamped at  50 mV, there was a sustained inward current (217 ± 6 pA; mean ± SEM) (Fig.
1a). This current disappeared
in normal Ringer's solution. The same current was obtained with
another membrane-permeant analog of cGMP [1 mM
8-p-chlorophenylthio-cGMP, which strongly resists hydrolysis by phosphodiesterase (PDE)] in the bath and also when the
recording pipette contained cGMP (Fig. 1d). A permeant
analog of cAMP was ineffective (n = 4). The cGMP-gated
current was observed in approximately half of the cells (37 of 73).
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Figure 1.
Stimulation of an AMPA receptor reduced a
sustained inward current caused by cGMP. a,
b, Puffer application of 100 µM glutamate
for 1 sec (thin arrows) or 100 µM AMPA
induced a fast transient inward current. Superfusion with 1 mM 8-bromo-cGMP (bars) activated a sustained
inward current that was reduced (thick arrows) by puffer
application of glutamate or AMPA. c, Application of 100 µM AMPA failed to reduce the 8-bromo-cGMP-induced
sustained current in the solution containing 100 µM CNQX.
d, Intracellular dialysis with 1 mM cGMP
caused a slowly developing inward current that was also reduced
(thick arrow) by puffer application of 100 µM AMPA. Whole-cell recording established at
t = 0. e, Normalized responses to
AMPA application plotted from b and d on
a faster scale. All cells were held at 50 mV.
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When the sustained cGMP-gated current was induced by 8-bromo-cGMP, a
puff of 100 µM glutamate evoked a biphasic response (Fig. 1a). First, there was a transient inward current, as
expected for direct gating of an ionotropic receptor; then, there was a brief reduction of the sustained inward current (41 ± 7%;
n = 5) (Fig. 1a). The same biphasic response
was evoked by AMPA (10-100 µM) (Fig. 1b) and
by the AMPA receptor agonist kainate (10 µM; n = 3). The amplitude of the second phase (reduced
inward current) was similar for 100 µM AMPA and 10 µM kainate (38 ± 6 and 34 ± 11%,
respectively, with 8-bromo-cGMP). The amplitude of the second phase was
also similar for 100 µM by AMPA and 100 µM
glutamate (54 ± 7 and 55 ± 8%, respectively, with cGMP).
However, when the sustained inward current was induced by
8-p-chlorophenylthio-cGMP, 100 µM AMPA did not
reduce the second phase of the response (3 ± 1%;
n = 3). The reduction by AMPA of the inward
current was faster (Fig. 1e, thick arrow)
when the sustained current was induced by cGMP rather than by
8-bromo-cGMP. The latency to maximal reduction after the AMPA puff was
4 ± 2 sec for cGMP and 11 ± 3 sec for 8-bromo-cGMP.
To identify which type of glutamate receptor reduced the inward
current, we applied various agonists and antagonists of the ionotropic
receptors. CNQX (100 µM), an antagonist of both AMPA and
kainate subtypes, diminished the effect of AMPA (n = 4)
(Fig. 1c). Furthermore, GYKI-52466 (100 µM), a
specific antagonist of the AMPA receptor (Donevan and Rogawski, 1993),
also diminished the effect of kainate (n = 3).
Therefore, kainate receptors are probably not involved. The AMPA
effects observed here, both the conventional transient inward current
and the novel reduction of the sustained inward current, seem to
desensitize rather little, as reported by others for AMPA responses of
bipolar and ganglion cells in mammalian retina (Cohen et al., 1994;
Sasaki and Kaneko, 1996). Finally, NMDA, applied as a 100 µM puff, evoked a monophasic inward current but did not
reduce the inward current (n = 4) (Fig. 2a). Thus, whatever causes
this brief reduction of the inward current, it is apparently triggered
specifically by the AMPA receptor.
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Figure 2.
The sustained inward current caused by cGMP was
unaffected by NMDA and mGluR agonists. a, Application of
100 µM NMDA for 1 sec from a puffer pipette
(arrows) failed to reduce the 8-bromo-cGMP-induced
sustained current. b, Application of 100 µM L-AP-4 (arrows) had no
effect on a cell before or during superfusion of 1 mM
8-bromo-cGMP. All cells were held at 50 mV.
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To test whether a metabotropic glutamate receptor (mGluR) might reduce
the inward current, we applied mGluR agonists. These included
L-AP-4 (n = 4) (Fig. 2b) and
ACPD (n = 3). Although these compounds evoke large
currents in ON bipolar cells (Nawy and Jahr, 1990; Shiells and Falk,
1990; Yamashita and Wässle, 1991; Tian and Slaughter, 1994) at
the concentration used (100 µM), they did not affect the
inward cGMP-gated current. Furthermore, mGluR antagonists MCPG and
CPPG, both applied at 300 µM, did not affect the
AMPA-evoked reduction of the steady inward current (n = 4). We conclude that the reduction by AMPA of the sustained inward current is not caused by activation of an mGluR.
If the reduction by AMPA of the sustained inward current results from
closing the cGMP-gated channel, both the reduction and the sustained
current should have the same reversal potential. The reduction by AMPA
of the sustained inward current was outward at negative potentials and
reversed at 0 mV (Fig. 3b).
Similarly, the sustained current induced by 8-bromo-cGMP was inward at
negative potentials and also reversed at approximately 0 mV (Fig.
3b). Similar values were obtained from four cells (3 ± 4 mV), consistent with a previous report (Ahmad et al., 1994). Thus,
both the cGMP-gated current and its AMPA-induced reduction reversed at
the same membrane potential (n = 4) (Fig.
3c), suggesting that AMPA suppresses the cGMP-gated current.
If so, AMPA should also suppress the sustained cGMP-gated current
induced by the NO donor, sodium nitroprusside, and we confirmed this
(n = 4) (Fig. 4).
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Figure 3.
AMPA-induced reduction of current reversed at the
same potential as the cGMP-gated current. a, Brief
current evoked by a puff of 100 µM AMPA was inward at
negative potentials and reversed at 0 mV. b, Same cell
in Ringer's solution containing 1 mM 8-bromo-cGMP. Slow
transient current evoked by AMPA was outward at negative potentials and
reversed at 0 mV. c, I-V curves of the
steady and reduced cGMP-gated currents. Both currents reversed at 2 mV.
These experiments suggest that AMPA actually suppresses the cGMP-gated
current.
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Figure 4.
Superfusion with 100 µM sodium
nitroprusside (SNP) activated a sustained inward current
reduced by puffer application of 100 µM AMPA for 1 sec (arrows). A cell was held at 50 mV.
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To investigate how the AMPA receptor suppresses the cGMP-gated current,
we considered a role for Ca2+ as a second messenger
(Kaupp and Koch, 1992; Nakanishi, 1992; Hille, 1994; Koutalos and Yau,
1996). If Ca2+ entering through the AMPA receptor
was involved, removing extracellular Ca2+ should
abolish the suppression. However, with 5 mM EGTA or BAPTA in a recording pipette, AMPA puffed onto a ganglion cell in
Ca2+-free Ringer's solution evoked the usual
suppression of the cGMP-gated current (n = 6) (Fig.
5a). AMPA (100 µM) reduced the current by 41 ± 7%, which
was similar to that in control Ringer's solution (38 ± 6%). The
latency (12 ± 4 sec) to maximal current reduction after the AMPA
puff was also similar to the control (11 ± 3 sec). When all
permeant cations were removed from the medium, 8-bromo-cGMP induced no
inward current at negative potentials; however, it did induce a
sustained outward current at positive potentials, and this current was
suppressed by AMPA. Thus, neither Ca2+ nor
Na+ influx is required for the suppression, and we
sought another mechanism.
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Figure 5.
The suppression by AMPA of the cGMP-gated current
is mediated by a G-protein that activates PDE. a,
Application of 100 µM AMPA (arrows)
suppressed the 8-bromo-cGMP-induced sustained current in the
Ca2+-free solution. The recording pipette contained
5 mM EGTA. b, Dialysis of a cell with 1 mM cGMP and 100 µM GTP--S produced an
inward current. An AMPA puff (arrow) evoked a brief
inward current and suppressed the sustained inward current
irreversibly. Whole-cell recording established at t = 0. c, Dialysis of a cell with pertussis toxin
(PTX; 1 µg/ml) and NAD+ (1 mM) also produced an inward current. An AMPA puff
(arrow) evoked a brief inward current but failed to
suppress the sustained inward current. d, Superfusion
with 100 µM IBMX (bar) activated an inward
current. An AMPA puff (arrows) also failed to suppress
the inward current induced by IBMX. All cells were held at 50
mV.
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We considered a role for a G-protein, possibly the Gi
family (Gi or Go), because AMPA can
stimulate Gi (Wang et al., 1997) and because the inner
plexiform and ganglion cell layers are immunoreactive for
Gi/o (Terashima et al., 1987; Vardi et al., 1993; Oguni et al., 1996). To test for a G-protein activity, we used 1 mM
cGMP in the patch pipette to cause a sustained inward current (as in Fig. 1d) but also included 100 µM GTP--S.
An AMPA puff induced the expected inward transient, followed by
suppression of the sustained current. However, when the AMPA
dissipated, the sustained current was not restored; rather, the
suppression became essentially irreversible (n = 4)
(Fig. 5b). This would be expected if an activated G-protein
had bound GTP--S because this GTP analog does not hydrolyze. In a
separate experiment with 1 mM cGMP in the pipette, we used 500 µM GDP--S to competitively block G-protein
activation (Nawy and Jahr, 1990). This produced a sustained inward
current, which AMPA failed to suppress (n = 3).
Evidence that the G-protein species might be Gi/o came from
experiments with pertussis toxin. Pertussis toxin ADP ribosylates Gi/o (Milligan, 1988), thereby blocking its downstream
effect. Dialyzing a cell with pertussis toxin and
NAD+ (omitting cGMP) produced a sustained inward
current, which AMPA also failed to suppress (n = 5)
(Fig. 5c). When NAD+ was omitted,
pertussis toxin alone failed to produce the effect (n = 3), suggesting that ADP-ribosylation by pertussis toxin of Gi/o induced the inward current. This effect of pertussis
toxin is consistent with previous results with ON bipolar cell (Shiells and Falk, 1992). Cholera toxin, which ADP ribosylates
Gs, caused no inward current until 8-bromo-cGMP was
added, and then the usual suppression was observed (n = 3). Because the cGMP-gated current seems to be suppressed by activating
Gi/o, we considered possible intermediate effectors.
PDE seemed a natural candidate, by analogy with photoreceptors and
certain bipolar cells in which a G-protein activates PDE to suppress a
cGMP-gated current (Yau and Baylor, 1989; Kaupp and Koch, 1992; Lamb
and Pugh, 1992; Koutalos and Yau, 1996). Furthermore, as noted,
suppression by AMPA of the inward current was faster when the sustained
current was induced by cGMP rather than by 8-bromo-cGMP (Fig.
1e). This would be expected from a PDE mechanism because the
brominated analog hydrolyzes slowly (Wei et al., 1998). The amplitude
of the current suppression was approximately similar for both
compounds. Although this might seem contradictory, the sluggish
hydrolysis of PDE of 8-bromo-cGMP may be counterbalanced by its sixfold
higher affinity for 8-bromo versus native cGMP (Wei et al., 1998).
These considerations led us to try inhibitors of PDE.
We found, as first reported by Ahmad et al. (1994), that the PDE
inhibitor IBMX induced a sustained inward current in a ganglion cell
that expresses the cGMP-gated channel (n = 4) (Fig.
5d). This implies that the cell also expresses an active PDE
that regulates intracellular cGMP. With IBMX in the bath, an AMPA puff
failed to suppress the inward current (n = 4) (Fig.
5d). We obtained the same result using a selective inhibitor
of cGMP phosphodiesterase, zaprinast (n = 3).
Presumably AMPA was ineffective because Gi/o could not
activate PDE. The suppression by AMPA of the cGMP-gated current was
observed when, to the bath containing 8-bromo-cGMP, we added 1 mM methylene blue, which completely inhibits guanylyl cyclase (n = 4) (Danziger et al., 1993; Fratelli et
al., 1995; Stuart-Smith et al., 1998). This result suggests that the
suppression does not involve modulation of the cyclase.
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DISCUSSION |
In ganglion cells that express the cGMP-gated channel, AMPA acts
in two ways: (1) transiently opens a cation channel; and (2) activates
a G-protein that, via PDE, reduces [cGMP] to suppress a cGMP-gated
current (Fig. 6). This second effect of
AMPA cannot be attributed to activation of a genuine mGluR receptor
because agonists and antagonists of mGluRs were ineffective. We feel
confident that a PDE is involved because the effect was abolished by
inhibitors of PDE and also by the analog of cGMP, which strongly
resists hydrolysis. In short, this AMPA receptor seems to exhibit both ionotropic and metabotropic activities. This conclusion fits
biochemical evidence that an AMPA receptor in cortex can activate a
G-protein to modulate cAMP (Wang et al., 1997) and that a kainate
receptor in hippocampus can activate a G-protein to modulate yet
another biochemical cascade (phospholipase C; Rodriguez-Moreno and
Lerma, 1998). Thus, metabotropic effects of ionotropic glutamate
receptors may prove to be both widespread and diverse.
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Figure 6.
Model explains how the AMPA receptor in retinal
ganglion cells might suppress the cGMP-gated current. NO released from
amacrine cells raises [cGMP] (Sagar, 1986), inducing the cGMP-gated
current (Ahmad et al., 1994). Ganglion cells express
Gi/o-coupled metabotropic receptors (shown by a
question mark), such as GABAB (Zhang et al.,
1997) and D2-dopamine receptor (Djamgoz and Wagner, 1992).
Unidentified link is shown with a broken arrow.
GLU, Glutamate; R, G-protein-coupled
receptor; G, Gi or Go
protein.
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Given that the suppression by AMPA of the cGMP-gated current acts via a
non-NMDA ionotropic glutamate receptor, can the family be identified?
Probably, it is the AMPA family (GluR1-4) because of the following:
(1) ganglion cells express mRNA for these subunits most strongly
(Hamassaki-Britto et al., 1993); (2) the concentrations of AMPA
(10-100 µM) were insufficient to activate native kainate receptors (Lerma et al., 1993; Clarke et al., 1997; Huettner, 1997);
and (3) the effect was blocked by GYKI-52466, which is relatively
specific for AMPA receptors. Which particular AMPA subunits (GluR1-4)
suppress the cGMP-gated current cannot be determined until their
specific agonists and antagonists become available.
AMPA receptors on CNS neurons desensitize rapidly (Colquhoun et al.,
1992; Raman and Trussell, 1992; Seeburg, 1993). Therefore, it surprised
us that, as in previous reports on mammalian retina (Cohen et al.,
1994; Sasaki and Kaneko, 1996), puff-applied AMPA causes little obvious
desensitization. However, the time course of our puff application is
slow compared with the rapid-flow method (Colquhoun et al., 1992; Raman
and Trussell, 1992) used to study desensitization. If our ganglion
cells desensitize in milliseconds, we would not see the effect. Another
possibility is that ganglion cells might express an alternatively
spliced "flip" module of the AMPA receptor, which desensitizes more
slowly than a receptor containing both "flip" and "flop"
modules (Sommer et al., 1990; Seeburg, 1993). Finally, a heteromer
of AMPA subunits (GluR1-4) and kainate subunits (GluR5-7 and KA1/2)
might resist desensitization.
How the AMPA receptor couples to the G-protein remains to be
established. Seven transmembrane receptors, including the mGluRs, contain a cytoplasmic tail with a conserved amino acid sequence that
binds the G-protein (Nakanishi, 1992; Hille, 1994; Riedel, 1996; Pass,
1998). However, the AMPA receptor is assembled from hetero-oligomers
that lack such a sequence (Sommer et al., 1990; Nakanishi, 1992;
Seeburg, 1993; Pass, 1998), so the AMPA receptor probably does not
affect the G-protein directly. Because there are now three examples in
which AMPA and kainate receptor families use a G-protein to trigger a
biochemical cascade (adenylyl cyclase, Wang et al., 1997; phospholipase
C, Rodriguez-Moreno and Lerma, 1998; PDE, present study), it will be
important to identify the coupling mechanism.
Approximately half of the recorded ganglion cells expressed the
cGMP-gated current, and all of these showed the AMPA-induced suppression. We identified ganglion cells in the slice by their location (ganglion cell layer) and large size (compared with displaced amacrine cells) but did not study their morphology. It will now be
interesting to determine which type(s) of ganglion cell express this
mechanism and to learn its role in visual processing. Possibly, NO
amacrine cells increase the cGMP-gated inward current of a ganglion
cell and thus enhance spiking. In a preliminary experiment, we indeed
observed that 8-bromo-cGMP had this effect. Glutamate from bipolar
cells can suppress the cGMP-gated current to briefly curtail these
extra spikes. Thus, the metabotropic action of the AMPA receptor might
contribute to suppress excitation from the NO amacrine cells.
Naturally, there are other possibilities, but this one emphasizes what
may be a general mechanism in many brain regions: that glutamate can
antagonize a key excitatory effect of NO.
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FOOTNOTES |
Received Dec. 16, 1998; revised Feb. 1, 1999; accepted Feb. 3, 1999.
This work was supported by National Institutes of Health Grant
EY00828. We thank N. Vardi, S. Zigmond, P. Liebman, D. Manning, S. Nawy, and A. Kaneko for comments; R. Smith, M. Freed, L. Haarsma, J. Demb, and J. Tanaka for technical advice; and S. Watanabe for technical
advice on the slice preparation.
Correspondence should be addressed to Dr. Fusao Kawai, c/o Dr. Peter
Sterling, 123 Anatomy/Chemistry Building, Department of Neuroscience,
School of Medicine, University of Pennsylvania, Philadelphia, PA
19104-6058.
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INTRODUCTION
