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The Journal of Neuroscience, 2001, 21:RC120:1-5
RAPID COMMUNICATION
 -Amyloid1-42 Peptide Directly Modulates Nicotinic
Receptors in the Rat Hippocampal Slice
D. L.
Pettit,
Z.
Shao, and
J. L.
Yakel
National Institute Of Environmental Health Sciences, National
Institutes of Health, Laboratory of Signal Transduction, Research
Triangle Park, North Carolina 27709
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ABSTRACT |
Alzheimer's disease (AD) is a human neurological disorder
characterized by an increasing loss of cognitive function and the presence of extracellular neuritic plaques composed of the  -amyloid peptide (A1-42). However, the link between these
molecular correlates of AD and the loss of cognitive function has not
been established. The pathology associated with AD includes the loss of
basal forebrain cholinergic neurons, presynaptic terminals in the
neocortex and hippocampus, and a decrease in the total amount of
neuronal nicotinic acetylcholine receptors (nAChRs). This leads to the
hypothesis that failure in the cholinergic system underlies the
dementia seen in AD. Cognitive performance has been linked to nAChR
function in the hippocampus, and the interneurons expressing nAChRs
coordinate the activity of large numbers of principal cells and
therefore have a powerful role in the regulation of hippocampal
activity. We have found that A1-42 inhibits whole-cell
and single-channel nicotinic currents from rat hippocampal interneurons
by directly blocking the postsynaptic nAChR channels at concentrations
as low as 100 nM. This inhibition appears specific for
peptide sequence and neuronal nAChRs, and the magnitude of A1-42 inhibition is dependent on the nAChR channel
subtype expressed. Thus, chronic inhibition of cholinergic signaling by A1-42 could contribute to the cognitive deficits
associated with AD.
Key words:
postsynaptic; photolysis; caged-carbachol; stratum
radiatum; interneurons; acetylcholine
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INTRODUCTION |
Nicotinic
acetylcholine receptors (nAChRs) are a multigene family of ligand-gated
ion channels (Le Novere and Changeux, 1995 ; Lindstrom, 1996) that
participate in various cognitive brain functions (Levin and Simon,
1998; Jones et al., 1999). Alzheimer's disease (AD) is a human
neurological disorder characterized by an increasing loss of cognitive
function and accompanied by various deficits in cholinergic
neurotransmission, including the loss of cholinergic neurons in the
basal forebrain, decrease in release of ACh, and decrease in choline
acetyltransferase activity (Auld et al., 1998; Selkoe, 1999). This
suggests that impairment of the cholinergic system may occur early in
AD and lead to cognitive deficits (James and Nordberg, 1995; Perry et
al., 1995; Francis et al., 1999; Paterson and Nordberg, 2000).
Other hallmarks of Alzheimer's disease include the presence of
extracellular neuritic plaques composed of the -amyloid peptide
(A1-42) and intracellular neurofibrillary tangles composed of tau protein. However, finding the link between these cellular markers and the loss of cognition has remained elusive.
Potential targets in AD pathology are the nAChRs because they are
widely expressed throughout the CNS, they are known to participate in
cognition, and AD patients exhibit decreased numbers (Le Novere and
Changeux, 1995; Levin and Simon, 1998; Jones et al., 1999; Paterson and Nordberg, 2000). Recently, it was reported that
A1-42 binds the  7 and non-7 subtypes of
nAChRs with high affinity (Wang et al., 2000a,b), but the physiological
significance of this binding was not investigated. We have examined the
effect of A1-42 on nAChR current in the rat
hippocampal slice. This region of the brain appears to play a prominent
role in cognition, learning, and memory tasks (Stewart and Fox, 1990;
Cobb et al., 1999). We determined previously that functional nAChRs are
preferentially expressed on the interneurons rather than the principal
cells in acute hippocampal slices (Jones and Yakel, 1997). Here we
demonstrate that A1-42 inhibits these
responses by directly blocking the postsynaptic nAChR channels. Chronic
inhibition of cholinergic signaling by A1-42
could contribute to the cognitive deficits and loss of cholinergic
function associated with Alzheimer's disease.
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MATERIALS AND METHODS |
Slice preparation. Standard techniques were used to
prepare 400-µm-thick slices from the hippocampus of 13- to 18-d-old
rats (Jones et al., 1999) and to make whole-cell patch-clamp
recordings from CA1 stratum radiatum interneurons. Pipettes were filled
with a solution that contained (in mM): 100 gluconic acid, 2-10 EGTA, 5 MgCl2, 2 Mg-ATP, 0.3 GTP, 40 HEPES; pH to 7.2 with CsOH. Slices were superfused at 21°C
with oxygenated physiological saline containing (in
mM): 119 NaCl, 2.5 KCl, 1.3 MgCl2, 2.5 CaCl2, 1 NaH2PO4, 26.2 NaHCO3, 11 glucose, and either caged-glutamate or
caged-carbachol (50 µM) (Molecular Probes,
Eugene, OR) (Milburn et al., 1989). In some experiments, 10 µM atropine was also added to block muscarinic AChR mediated responses. In photolysis experiments, dose-response curves were constructed by adding A1-42 or
A12-28 (RBI/Sigma, St. Louis, MO; prepared
just before use) peptide incrementally to increase the concentration
from 250 to 500 nM, 1 µM,
and 2 µM. Data were normalized relative to the
amplitude of the initial response. Recordings were analyzed only if the
holding current was <100 pA when cells were voltage-clamped at  70 mV.
To eliminate the possibility that the caged-carbachol could itself
desensitize nAChRs, nAChR-mediated synaptic transmission was elicited
by electrical stimulation followed by the addition of 50 µM caged-carbachol to the bath solution. The
caged-carbachol had no effect on the amplitude of the synaptic
responses, suggesting that it did not desensitize nAChRs (data not
shown). For pressure application experiments, ACh was applied using the
Burleigh PZ-150M piezo electric device. ACh (1 mM for 3 sec) was used to elicit nAChR currents at 3 min
intervals. Dose-response curves were constructed by switching from ACh
to ACh/A1-42 solutions containing 50, 100, 250, 500 nM, and 1 µM
A1-42. To test for reversal of the
A1-42 inhibition, we then switched back to
the ACh solution.
Local photolysis. The 351-364 nm output of a continuous
emission 8 W argon ion laser (Spectraphysics Model 165) was delivered, via a multimode optical fiber, through an Olympus 40× water-immersion objective to form an uncaging spot 7.5 µm in diameter. An electronic shutter (Uniblitz) was used to vary the duration of the light pulse
(2-6 msec). The uncaging spot was positioned over a cellular process
by including a fluorescent dye (Oregon Green-1, 200 µM; Molecular Probes) in the patch pipette
solution and then visualizing the cell with a cooled CCD camera
(Sensicam). To avoid possible phototoxic effects, illumination was kept
to a minimum.
Single-channel recordings. The single-channel outside-out
patch-clamp configuration was used to pull patches from the soma of
hippocampal CA1 stratum radiatum interneurons (Shao and Yakel, 2000).
Pipettes had resistances of 5-10 M when back-filled with pipette
solution containing (in mM): 140 cesium
gluconate, 10 HEPES, 2 MgCl2, 0.5 CaCl2, 5 BAPTA, and 2 Mg-ATP, pH 7.2 adjusted with CsOH. Single-channel currents were obtained using an Axopatch 200B
amplifier (Axon Instruments), low-pass-filtered at 5 kHz, and digitized
at 20 kHz. All data were acquired and analyzed with pClamp 8 software
(Axon Instruments). The average amplitudes of single-channel currents
were measured using an all-points histogram well fitted by Gaussian
distributions. The open channel probability (Po) was estimated from the event
lists determined with the Fetchan program. The detection of events was
determined by the "50% threshold" method. Data were collected from
a total of eight patches from eight cells. Single-channel measurements
were made by sampling for 3-10 sec for each patch and each condition.
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RESULTS |
The nicotinic responses of CA1 interneurons in slices of rat
hippocampus desensitize rapidly, particularly the 7 receptor subtype
(Alkondon et al., 1997; Jones and Yakel, 1997; Frazier et al., 1998a;
Ji and Dani, 2000). Therefore, we chose to elicit nicotinic currents
from stratum radiatum interneurons by local photolysis (Wang and
Augustine, 1995; Pettit et al., 1997) of caged-carbachol (50 µM). This method allows us to isolate postsynaptic nAChRs
(Alkondon et al., 1998; Frazier et al., 1998b) and induce rapid, brief
activation of nAChRs with minimal desensitization. Brief pulses (2-5
msec) of UV light were delivered from a continuous emission argon ion
laser at 3 min intervals, under whole-cell voltage-clamp conditions.
All caged-carbachol-induced currents can be blocked by curare (10 µM) and high, nonselective concentrations of
methyllycaconitine (MLA; 500 nM), demonstrating that they
are caused by activation of nAChRs. Many of these currents require both
50 nM MLA and dihydro--erythroidine (10 µM) for complete block, suggesting that they are caused
by activation of both 7 and non-7 subtypes of nAChRs. However, some currents are completely blocked by 50 nM MLA (Fig.
1A). Previously published single-channel and whole-cell nAChR data suggest that ~70%
of the nAChRs on interneuron cell bodies are the 7 subtype, whereas
30% are the non-7 subtype (Jones and Yakel, 1997; Shao and
Yakel, 2000). These data suggest that only nAChR-mediated currents are
evoked by uncaging caged-carbachol and that diverse subtypes (i.e.,
both 7 and non-7) are being activated (Fig. 1A).
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Figure 1.
A1-42 blocks current through
nAChRs. A, Nicotinic currents evoked by local photolysis
of caged-carbachol. Some currents are completely blocked by application
of 50 nM MLA (top) and some are only
partially blocked (bottom). B, Plot of
nicotinic current amplitude during control period and after application
of A1-42 (2 µM). C,
Averaged response amplitude before and after application of 2 µM A1-42 (n = 5).
D, The block of nicotinic current is dose dependent.
Averaged amount of block elicited by varying concentrations of
A1-42 (n = 3). Whole-cell currents
were elicited by pressure application of 1 mM ACh and
A1-42.
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A1-42 inhibits carbachol-induced current
Does the binding of A1-42 to nAChRs
affect current through these receptors? An initial application of
A1-42 (1 µM) reduced current
amplitude by 40% when added to the perfusate after a baseline response
was established (Fig. 1B,C). The
addition of a higher dose of A1-42 (2 µM) produced no further increase in the current
block. We subsequently determined that block of nAChRs by
A1-42 was dose dependent, with a maximum of
39 ± 3% at a dose of 500 nM. Application
of a lower dose (250 nM) of the peptide produced
a 20 ± 3% block. We have also examined the effect of
A1-42 on whole-cell nicotinic currents
elicited by pressure application of ACh and
A1-42. Using this method, nAChR currents were
also inhibited in a dose-dependent manner (Fig. 1D).
At 50 nM, A1-42 had no
effect on current amplitude, but a concentration of 100 nM inhibited currents by 32 ± 4%. Pressure application of A1-42 produced a higher level
of inhibition, 59 ± 7% (Fig. 1D)
(n = 3), at a concentration of 1 µM when compared with 35 ± 5%
(n = 4) with the uncaging method. It is possible that
the higher doses of ACh delivered by pressure application (as evidenced
by currents lasting tens of seconds) may have produced some receptor
desensitization, which contributed to this discrepancy. Together these
data are consistent with high-affinity binding of
A1-42 to nAChRs that leads to an inhibition
of postsynaptic nAChR-mediated current.
A1-42 inhibition is reversible
The inhibition of nAChR currents by
A1-42 is rapidly reversible under whole-cell
conditions. Figure 2A
illustrates an experiment in which nicotinic whole-cell currents were
elicited from hippocampal slice interneurons by pressure application of 1 mM ACh. After a baseline was established, ACh + A1-42 (50 nM) were
applied, inhibiting the whole-cell current by 40%. After the removal
of A1-42, complete recovery occurred within 6 min (Fig. 2A). The total amount of recovery varied
between cells from 60 to 100%.
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Figure 2.
A1-42 block is reversible,
specific, and mimicked by the truncated peptide A12-28.
A, The inhibition of whole-cell currents by
A1-42 is reversible. Individual responses were elicited
by either ACh or ACh + A1-42 (100 nM).
Complete reversal of the block was observed 6 min after removal of
A1-42. B, A12-28 blocks
currents elicited by uncaging caged-carbachol in a dose-dependent
manner. C, Nicotinic currents induced by local
photolysis of caged-carbachol are not affected by 2 µM
A40-1. D, A1-42 (2 µM)
does not affect glutamate currents evoked by local photolysis of
caged-glutamate (15 sec intervals).
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A12-28 also inhibits carbachol-induced current
To explore which region of A1-42
inhibits nAChRs, we tested the ability of a peptide
fragment, A12-28, to
block nAChR current. Previous work has demonstrated that
A12-28 interferes with the binding of
A1-42 to the nAChRs (Wang et al., 2000a).
A12-28 was also able to inhibit current amplitude in a dose-dependent manner (Fig. 2B). The
maximal amount of current block was increased to 95 ± 2% (Fig.
2B) (n = 5). The apparent increased
effectiveness of the short peptide may be caused by differences in
binding affinity, or it may reflect better access of the shorter
peptide to the extracellular space within the slice. Taken together,
these data demonstrate that A1-42 directly modulates postsynaptic nAChRs and that this modulation is mediated by
the fragment including amino acid residues 12-28.
A1-42 inhibition is specific for peptide sequence
and nicotinic receptors
We next examined whether A1-42 inhibited
nAChRs by a direct postsynaptic interaction or through nonspecific
interactions. First, the specificity of amino acid sequence was tested.
A 40 amino acid peptide with a sequence that was the reverse of
A1-42 was used.
A40-1 had no effect on carbachol-induced
current amplitude (Fig. 2C) (n = 3). This is
in accord with previous work demonstrating that
A40-1 does not mimic the effects of A1-42 (Auld et al., 1998). In a further test
of specificity, we examined the ability of
A1-42 to modulate ligand-gated ion channels
other than nAChRs. A1-42 (2 µM) had no effect on the amplitude or time
course of currents elicited by local photolysis of caged-glutamate
(Fig. 2D) (n = 4). The inability of
A1-42 to modulate glutamate currents and the
ineffectiveness of A40-1 indicates that block
of current amplitude by A1-42 is specific for
nAChRs and peptide sequence. Because carbachol activates both
muscarinic and nicotinic receptor types, we also tested whether the
observed inhibition of current occurred through a muscarinic
receptor-associated pathway. In some experiments, 10 µM atropine was used to block muscarinic
receptors. Atropine had no effect on the inhibition of nicotinic
currents by A1-42 (data not shown). These
data further support a direct, inhibitory interaction of
A1-42 with postsynaptic nAChRs.
A1-42 decreases open channel probability
of nAChRs
To investigate the mechanism of current block by
A1-42, we examined its effect on the
single-channel properties of nAChRs in outside-out patches that were
excised from stratum radiatum interneurons in hippocampal slices (Shao
and Yakel, 2000). Channels were activated by pressure application of 10 µM ACh for 30 sec. We observed two different channel
types: one with a single-channel conductance of 38 pS and another with
a 62 pS conductance (Fig. 3A).
A1-42 (2 µM) reduced
the Po of both channel types within
milliseconds of ACh application. The block was partially reversible,
probably because of channel rundown (Fig. 3A) (Shao and
Yakel, 2000). These data further support the hypothesis that A1-42 inhibits nAChR current by binding
directly to nAChRs with high affinity and specificity.
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Figure 3.
A1-42 reduces nAChR open channel
probability. A, Single-channel responses to ACh (10 µM) before, during, and after application of 2 µM A1-42 for both channel types. For the
38 pS channel, Po was 0.2 (Control), 0.15 (+A1-42), and 0.17 (Wash). For the 62 pS channel,
Po was 0.006 (Control), 0.003 (+A1-42), and 0.004 (Wash). B, Average block of
Po after application of
A1-42 for both channel types. The frequency of channel
opening (sec 1) for the 38 pS
channel before, during, and after A1-42 application was
870 ± 550, 707 ± 420, and 1150 ± 740, respectively.
For the 62 pS channel, these values were 77 ± 30, 45 ± 20, and 50 ± 20, respectively.
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The magnitude of the inhibition is dependent on the receptor
subtype expressed
To determine the nAChR subtype composition and sensitivity to
A1-42, we applied the 7-specific
antagonist MLA (50 nM) to excised patches. As expected from
our previous work (Shao and Yakel, 2000), activation of the 38 pS
channel by ACh (10 µM) was sensitive to MLA, indicating
that it contained the 7 nAChR subunit. The 62 pS channel was
insensitive to block by MLA, suggesting that this channel did not
contain the 7 subunit. A1-42 effectively
decreased the Po at both 7 and
non-7 subtypes, consistent with the idea that
A1-42 binds and inhibits multiple subtypes of
nAChRs (Fig. 3B) (Wang et al., 2000b). However, the
magnitude of channel inhibition was dependent on the receptor subtype.
A1-42 reduced
Po of the 38 pS channel by 14 ± 8% (n = 5) while Po
of the 62 pS channel was reduced by 54 ± 15% (Fig.
3B) (n = 3). The frequency of channel
opening was also decreased by 16 ± 9% and 32 ± 20%,
respectively. The decrease in channel block by
A1-42 for the 38 pS channel was significantly
different from that of the 62 pS channel (p < 0.05; Student's t test). On the basis of our previous work
as well as the current study, we found that 70% of the nAChRs are the
38 pS (MLA sensitive) subtype and 30% are the 62 pS subtype. Assuming
that the channels are coexpressed on most neurons, as suggested by our
whole-cell data, we would predict an inhibition of 26% [(0.70 × 0.14) + (0.30 × 0.54)]. The average observed
inhibition of the carbachol-induced currents was 39 ± 3%, which
appears somewhat larger, but it is possible that we have underestimated
the level of 7 inhibition because channels in patches may not be
regulated in the same fashion as channels in the whole-cell configuration.
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DISCUSSION |
We have provided evidence of a novel physiological role for
A1-42 as an inhibitor of postsynaptic nAChRs
in rat hippocampal interneurons. A1-42
blocked nAChR-mediated current and reduced open channel probability.
The inhibition of nAChR-mediated current is specific for
A1-42 and nAChRs, suggesting a direct
modulation of nAChRs, probably through the amino acid residues 12-28
of A1-42. This modulation occurs rapidly,
within milliseconds at single channels, and in <3 min in brain slices. The amount of inhibition is dependent on the subtype of receptor being
expressed. Together these data are consistent with high-affinity binding of A1-42 to nAChRs that leads to an
inhibition of postsynaptic nAChR-mediated current. Because expression
of nicotinic receptor subtypes in the brain can vary with genetic patterns and environmental exposure (Slotkin, 1998), the susceptibility to block by A1-42 may also vary from
individual to individual.
A1-42 was an effective inhibitor of nicotinic
currents at concentrations as low as 100 nM. The
physiological relevance of this concentration depends on two factors:
(1) the actual concentration of A1-42 within
the brain slices and (2) the concentration of
A1-42 in AD brain tissue. Both of these
factors are difficult to determine with a high degree of certainty. We
were unable to determine the exact A1-42
concentration within the brain slice tissue, but it is likely that
A1-42 concentration is significantly lower
than that of the bath solution because of restricted diffusion and
access to the extracellular space. Accurate estimates of
A1-42 concentrations in AD brain tissue are
also difficult to determine, but transgenic animals expressing mutant
forms of human amyloid precursor protein have A concentrations
estimated in the low nanomole range (10-50 nM) (Hsia et
al., 1999; Mucke et al., 2000). However, this measure may be an
underestimate of A1-42 concentration because these values were determined with a global tissue assay. A
distribution is unlikely to be completely random and uniform throughout
the brain. As a result, concentrations in targeted regions of the brain
or at synaptic release sites may be much higher.
Previously published binding data (Wang et al., 2000a,b) suggests that
A1-42 binds to nAChRs in the low picomole
range for 7 and in the 20-30 nM range for non-7
nAChRs. We observed inhibition of the non-7 receptors at
concentrations only three- to fivefold higher than the binding data.
However, ligand-binding measurements do not access function. Many
receptors require the binding of multiple ligands before channels open,
and binding affinity is often dependent on the receptor state (Chang
and Weiss, 1999). Standard binding assays usually use membrane
preparations that may alter the regulation and conformation of the
channels. Taken together with the uncertainty of actual tissue levels
of A1-42, our effective concentrations are
consistent with the binding data for non-7 receptor subtypes. The
extremely high-affinity binding reported for 7 is more difficult to reconcile.
We currently favor a direct mechanism of action by
A1-42 because of its effect on excised,
outside-out, cell-free membrane patches, and the direct binding to
multiple subtypes of nAChR channels previously demonstrated (Wang et
al., 2000b). Other mechanisms of action are possible through various
different signal transduction cascades known to be regulated by
A1-42 (e.g., G-protein and free radical
pathways). However, such pathways are unlikely to be functioning in our
excised patches.
It remains unclear which form of A1-42 (i.e.,
fibrillar vs soluble) is toxic. Initial reports suggested that only
fibrillar amyloid was neurotoxic (Lorenzo and Yankner, 1994), but
recent evidence (Roher et al., 1996) suggests that it is the soluble oligomeric form of A that may be neurotoxic. We are unable to conclusively state which form of A1-42 is
binding to nAChRs in our experiments. Because we prepared our
A1-42 solutions just before use, and because
the fibrillar form of A1-42 would have very
poor access to the extracellular space in brain slice tissue, we
believe that the nAChRs are inhibited by the soluble, oligomeric form
of A1-42. The very rapid onset of the
inhibition at single channels (20 msec) is also consistent with this hypothesis.
Our results may provide a mechanistic explanation for the early
cognitive deficits seen in AD patients long before plaque formation
(Hsia et al., 1999; Naslund et al., 2000). Early cognitive effects have
also been seen in transgenic animals in which behavioral deficits
precede amyloid deposition, and some individuals have neuritic plaques
without the cognitive deficits associated with AD (Hardy, 1997).
A1-42 also inhibits the best-characterized form of cellular learning and memory: long-term potentiation (Chen et
al., 2000). All of these data suggest that
A1-42 might exert its cognitive effects
independently of plaque formation (Naslund et al., 2000). In contrast,
the neurotoxic effects of A1-42 are often
associated with the fibrillar form [but see Roher et al. (1996); Auld
et al. (1998)]. Initiation of neurotoxic events usually requires
longer exposures and higher doses of A1-42, probably initiating a number of signal transduction pathways that may
differ from those underlying cognitive impairment.
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FOOTNOTES |
Received Sept. 5, 2000; revised Oct. 18, 2000; accepted Oct. 20, 2000.
This work was supported by the National Institutes of Health intramural
program. We thank D. Armstrong for scientific discussions and helpful
comments. We also thank C. Erxleben, L. McMahon, S. Sudweeks, F. Schweizer, and S. White for helpful comments on an earlier version of
this manuscript.
Correspondence should be addressed to Jerrel L. Yakel, National
Institute Of Environmental Health Sciences, National Institutes of
Health, Laboratory of Signal Transduction, 111 TW. Alexander Drive,
Research Triangle Park, NC 27709. E-mail:
yakel{at}niehs.nih.gov.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 2001, 21:RC120 (1-5). The
publication date is the date of posting online at
www.jneurosci.org.
| |
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Copyright © 2000 Society for Neuroscience 0270-6474/00/$05.00/0
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ABSTRACT
INTRODUCTION
