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The Journal of Neuroscience, August 1, 2001, 21(15):5568-5573
Associative Learning Elicits the Formation of Multiple-Synapse
Boutons
Yuri
Geinisman1,
Robert
W.
Berry1,
John F.
Disterhoft1,
John M.
Power2, and
Eddy A.
Van der
Zee3
1 Department of Cell and Molecular Biology,
Northwestern University Medical School, Chicago, Illinois 60611, 2 Division of Neuroscience, John Curtin School of Medical
Research, Australian National University, Canberra ACT 2601, Australia,
and 3 Department of Zoology, University of Groningen, 9751 NN Haren, The Netherlands
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ABSTRACT |
The formation of new synapses has been suggested to underlie
learning and memory. However, previous work from this laboratory has
demonstrated that hippocampus-dependent associative learning does not
induce a net gain in the total number of hippocampal synapses and,
hence, a net synaptogenesis. The aim of the present work was to
determine whether associative learning involves a specific
synaptogenesis confined to the formation of multiple-synapse boutons
(MSBs) that synapse with more than one dendritic spine. We used the
behavioral paradigm of trace eyeblink conditioning, which is a
hippocampus-dependent form of associative learning. Conditioned rabbits
were given daily 80-trial sessions to a criterion of 80% conditioned
responses in a session. During each trial, the conditioned stimulus
(tone) and the unconditioned stimulus (corneal airpuff) were presented
with an intervening trace interval of 500 msec. Brain tissue was taken
for morphological analyses 24 hr after the last session. Unbiased
stereological methods were used for obtaining estimates of the total
number of MSBs in the stratum radiatum of hippocampal subfield CA1. The
results showed that the total number of MSBs was significantly
increased in conditioned rabbits as compared with pseudoconditioned or
unstimulated controls. This conditioning-induced change, which occurs
without a net synaptogenesis, reflects a specific synaptogenesis
resulting in MSB formation. Models of the latter process are proposed.
The models postulate that it requires spine motility and may involve
the relocation of existing spines from nonactivated boutons or the
outgrowth of newly formed spines for specific synaptogenesis with
single-synapse boutons activated by the conditioning stimulation.
Key words:
associative learning; trace eyeblink conditioning; hippocampus; CA1 stratum radiatum; multiple-synapse boutons; synaptic
plasticity; synaptogenesis; spine motility
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INTRODUCTION |
More than a century ago, cellular
mechanisms of learning and memory were postulated to include both the
establishment of new synaptic connections and the restructuring of
existing ones to make them more efficacious (Ramón y Cajal, 1893 ;
Tanzi, 1893). Subsequent electron microscopic studies have indicated
that both types of synaptic alteration may occur in pertinent regions
of the vertebrate brain as a consequence of behavioral learning (for review, see Greenough and Bailey, 1988; Bailey and Kandel, 1993; Andersen and Soleng, 1998; Klintsova and Greenough, 1999; Geinisman, 2000). However, some studies have failed to demonstrate a
learning-related increase in total synapse number on the basis of
analyses of samples from the entire synaptic population of a given
brain region (for review, see Geinisman, 2000). This suggests that a
net synaptogenesis may not necessarily underlie the formation of
memories after the learning of some behavioral tasks. It is conceivable
that in such cases, learning-induced synaptogenesis may be confined to
rearranging only a specific subset of synaptic connections to establish
a memory trace.
A specific synaptogenesis of this kind may involve the formation of
multiple-synapse boutons (MSBs). Such boutons form separate synapses
with two or more postsynaptic elements instead of only one synapse with
a single postsynaptic element, as is the case for single-synapse
boutons. The results of earlier studies indicate that the incidence of
MSBs is increased in rat cerebellar and motor cortices after
acquisition of complex motor skills (Federmeier et al., 1994; Jones et
al., 1999) and in the visual cortex of rats housed in a complex
environment (Jones et al., 1997). It has also been demonstrated (Toni
et al., 1999) that the proportion of MSBs is increased after the
induction of hippocampal long-term potentiation (LTP), which is widely
regarded as a synaptic model of memory (Bliss and Collingridge,
1993).
In light of these observations, we decided to explore the possibility
that hippocampus-dependent associative learning, which does not alter
the total number of synapses in the CA1 stratum radiatum (Geinisman et
al., 2000) and, hence, does not involve a net synaptogenesis,
nevertheless induces a specific synaptogenesis leading to the formation
of MSBs. For this purpose, we reexamined electron micrographs obtained
in our previous study (Geinisman et al., 2000). In that study, the
behavioral paradigm of trace eyeblink conditioning was used. Lesions of
the hippocampus have been shown to prevent acquisition of the trace
eyeblink conditioned response in rabbits (Solomon et al., 1986; Moyer
et al., 1990; Kim et al., 1995). Moreover, electrophysiological
recordings made from rabbit hippocampal slices have revealed that trace
eyeblink conditioning is accompanied by increases in the synaptic
responsiveness (Power et al., 1997; Geinisman et al., 2000) and
postsynaptic excitability (Disterhoft et al., 1986; Moyer et al., 1996)
of CA1 pyramidal neurons. Therefore, in the present study we determined whether additional MSBs are formed in the CA1 stratum radiatum of those
rabbits that acquired the trace eyeblink conditioned response. We
provide evidence for a conditioning-induced increase in the total
number of MSBs in the synaptic layer examined.
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MATERIALS AND METHODS |
Experimental animals and behavioral training. Female
New Zealand albino rabbits (Oryctolagus cuniculus) of 8-10
weeks of age were purchased from Hazelton Rabbitry (Denver, PA). All
procedures related to the care and treatment of animals were approved
by the Animal Care and Use Committee of Northwestern University and performed in accordance with the guidelines of the National Institutes of Health. Rabbits were trained in pairs in individual sound-attenuated chambers and received either trace eyeblink conditioning or, as a
control, pseudoconditioning according to an established experimental protocol (Thompson et al., 1996; Moyer et al., 2000). Conditioned rabbits were given daily training sessions, each consisting of 80 trials with a randomly determined intertrial interval between 30 and 60 sec, which was adjusted to give a mean of 45 sec. During each trial,
the conditioned stimulus (CS; 100 msec, 85 dB, 6 kHz tone) not only
preceded the unconditioned stimulus (US; 150 msec, 3.0 psi corneal
airpuff) but was also separated from it by a stimulus-free, or
"trace," interval of 500 msec. An eyeblink response was considered to be conditioned if it occurred after CS onset and before US onset.
Conditioned animals were trained until they reached a learning criterion of 80% conditioned responses during a training session. A
total of 5-10 sessions were required to reach criterion.
Pseudoconditioned rabbits received explicitly unpaired presentations of
the same CS and US that were used in conditioning. Each daily session
of pseudoconditioning consisted of 80 CS-alone and 80 US-alone trials. Both the CS and the US were administered in pseudorandom order at a
variable intertrial interval that averaged 22.5 sec. The timing of each
stimulus was determined independently to ensure the same probability of
the CS preceding the US and of the US preceding the CS.
Pseudoconditioned rabbits were session-matched with their conditioned
counterparts to control for nonspecific effects such as sensitization.
The animals were coded and transcardially perfused for microscopy 24 hr
after the last training session.
Tissue preparation. The protocols for perfusion fixation and
tissue processing, as well as for unbiased stereological sampling and
counting, have been described in detail earlier (Geinisman et al.,
1996, 2000), and only a brief account of these procedures is
given below. Animals were deeply anesthetized with a combination of
xylazine (6 mg/kg, i.m.) and ketamine hydrochloride (45 mg/kg, i.m.),
followed 15 min later by pentobarbital sodium (75 mg/kg, i.m.). They
were then transcardially perfused with the following consecutively
administered solutions: PBS containing heparin sodium (10 U/ml), an
aldehyde fixative (1% paraformaldehyde, 1.25% glutaraldehyde, and
0.02 mM CaCl2 in 0.12 M phosphate buffer, pH 7.3), and the same
fixative at twice the aldehyde concentration. The left hippocampal formation was dissected free and physically straightened to diminish its natural curvature, which produced no apparent mechanical damage to
the fixed tissue and did not cause alterations in the ultrastructure of
tissue components as compared with tissue treated without this manipulation. The straightened hippocampal formation was cut, perpendicular to its septotemporal axis, into 11-14 consecutive slabs,
each 1.5 mm thick. The position of the first cut within the first 1.5 mm interval from the septal pole was selected randomly, and the
subsequent cuts were placed at a uniform interval from each other. The
slabs were treated with OsO4, dehydrated in
ethanol solutions of increasing concentrations, and flat-embedded in Araldite.
Estimation of the total volume of the CA1 stratum radiatum.
This procedure was performed at the light microscopic level according to the Cavalieri principle. The thickness of embedded slabs was measured in an inverted microscope at a final magnification of 18×.
Then, 3-µm-thick sections were prepared from the septal face of
tissue slabs, stained with Azur II-methylene blue, and used to estimate
the area of sectional profiles of the CA1 stratum radiatum by point
counting. The volume of CA1 stratum radiatum was calculated as the
product of the sum of profile areas and the mean thickness of embedded slabs.
Stereological sampling and counting of MSBs. In each animal,
MSBs were sampled in six fields that were positioned randomly along the
septotemporal axis and in a systematic random manner along the other
two (CA2-subicular and cell body-apical dendrite) axes of the CA1
stratum radiatum. A total of 31-38 consecutive ultrathin sections were
prepared from each sampling field and used to obtain electron
micrographs (final magnification, 20,000×). Each micrograph series was
assigned a code number to be decoded after completion of all analyses.
Initially, MSBs were identified on micrographs of serial sections as
single axonal swellings that contained synaptic vesicles and formed
synapses with two or more dendritic spines. An apposition between an
MSB and a spine was classified as a synapse if the spine exhibited a
postsynaptic density. Then MSBs were counted with disectors.
Each disector consisted of electron micrographs of two adjacent serial
sections. The mean area of the disector counting frame was 80.0 µm2. The mean disector height, i.e., the
thickness of a reference section, was 0.080 µm, as estimated with
Small's technique of minimal folds (Royet, 1991). Thus, the mean
disector volume was equal to 6.40 µm3.
From each section series, 15 consecutive sections were selected with a
random start from section 3, 4, or 5 and used as reference sections of
disectors. The last 12-20 sections of each series were not used as
reference sections to ensure that all counted MSBs were included in
their entirety in the section series. Sections immediately preceding
the reference ones were used as look-up sections of disectors. An MSB
was counted if its profile was seen on a reference section micrograph
but was not observed on a look-up section micrograph. A sample of
32-53 MSBs (mean = 45) was obtained from each animal.
Estimation of the numerical density and the total number of MSBs
in the CA1 stratum radiatum. The numerical density of MSBs per
unit volume was calculated as their mean number counted per disector
divided by the mean disector volume. The parameter of total MSB number
was calculated as the product of CA1 stratum radiatum volume and the
numerical density of MSBs.
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RESULTS |
Total MSB number is increased in the CA1 stratum radiatum of
conditioned rabbits relative to pseudoconditioned controls
Examination of electron micrographs of the rabbit CA1 stratum
radiatum revealed that some presynaptic boutons made synapses with two
or more postsynaptic elements. A typical MSB in this layer is a single
presynaptic bouton that forms separate synapses with two spine heads
(Fig. 1). Such MSBs can be unequivocally identified only in serial sections because in single sections they
usually exhibit synapses with one spine (Fig.
1A,C) and less frequently with two
spines (Fig. 1B). MSBs synapsing with a dendritic shaft and a spine were encountered extremely rarely because
axodendritic synapses constitute only ~2% of the entire synaptic
population of the CA1 stratum radiatum (Geinisman et al., 2000).
Therefore, only those MSBs that formed synapses exclusively with spines
were quantified. The results showed that the total number of MSBs was increased by 18.1% in the group of conditioned rabbits as compared with the pseudoconditioned group (Table
1) and that this change was statistically
significant [p( =
0.05) = 0.0195, two-tailed randomization test for matched
pairs (Siegel, 1956)].
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Figure 1.
A-C, Electron micrographs of
consecutive ultrathin sections demonstrating a multiple-synapse bouton
(MSB) that makes synapses (arrows) with
two dendritic spines (SP1 and SP2). Scale
bar, 0.2 µm.
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View this table:
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Table 1.
Total number of MSBs (× 106) in the CA1
stratum radiatum of pseudoconditioned (PC) and conditioned (CD) rabbits
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Total MSB number is increased in the CA1 stratum radiatum of
conditioned rabbits relative to untrained controls
The difference in MSB number between the two groups of animals
might be attributable to an increase in the conditioned rabbits or to a
decrease in the pseudoconditioned ones. To clarify this issue, a
separate group of five untrained control rabbits was examined. The
estimates of the total MSB number obtained from individual untrained
animals (1135, 1102, 1223, 923, and 1002 × 106) were comparable with those obtained
from the pseudoconditioned controls (Table 1). Kruskal-Wallis one-way
ANOVA by ranks (Siegel, 1956; Winer et al., 1991) on the differences
among the three groups showed that they were statistically significant
[H(df = 2) = 8.992, p = 0.0112]. After the overall Kruskal-Wallis test,
comparisons between various groups that were taken two at a time were
made with the Mann-Whitney U test (Winer et al., 1991).
These comparisons revealed that the conditioned rabbits had
significantly more MSBs as compared with either untrained (U = 6.00, Z =  2.20, p = 0.0278) or pseudoconditioned
(U = 10.00, Z = 2.69, p = 0.00708)
controls. On the other hand, the two control groups did not differ
significantly from each other with respect to total MSB number (U = 17.00, Z = 0.733, p = 0.463). Accordingly, the
mean values (±SEM) of this parameter estimated for the groups of
untrained and pseudoconditioned rabbits (1077 ± 52 and 1047 ± 28 × 106, respectively) differed
by only 2.8%. These data indicate that the observed difference between
conditioned and pseudoconditioned animals does reflect a
conditioning-induced increase in the total number of MSBs.
Synapse number per MSB is not affected by trace
eyeblink conditioning
Although MSBs in the rabbit CA1 stratum radiatum usually form
synapses with two spines, some MSBs synapse with three spines, and on
two occasions four postsynaptic spines were seen in contact with a
single MSB. We addressed the question of whether trace eyeblink
conditioning changes the number of axospinous synapses per MSB.
Comparison of pseudoconditioned and conditioned rabbits showed that the
mean numbers (±SEM) of axospinous synapses per MSB were the same for
the two groups of animals (2.05 ± 0.01 and 2.05 ± 0.02, respectively).
Trace eyeblink conditioning does not change the number of
perforated axospinous synapses per MSB
Axospinous synaptic contacts established by MSBs include
perforated synapses, which exhibit a discontinuous profile of the postsynaptic density in at least one serial section, and nonperforated synapses that show a continuous postsynaptic density profile in all
consecutive sections. The perforated subtype has been implicated in
synaptic plasticity that is associated with behavioral learning and
hippocampal LTP (for review, see Jones and Harris, 1995; Geinisman, 2000). We estimated the number of perforated synapses per MSB and found
that the groups of pseudoconditioned and conditioned animals did not
differ significantly on this measure [group means ± SEM were
0.375 ± 0.036 and 0.339 ± 0.035, respectively;
p( = 0.05) = 0.426, two-tailed randomization test for matched pairs].
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DISCUSSION |
Associative learning involves a specific synaptogenesis that
results in the formation of MSBs
The major finding of this study is that trace eyeblink
conditioning is accompanied by an increase in the total number of MSBs in the CA1 stratum radiatum. For MSBs to be formed, some axonal boutons
and dendritic spines must make new synaptic contacts with each other.
Therefore, the data presented here are consistent with the idea that
hippocampus-dependent associative learning induces a specific
synaptogenesis resulting in the formation of MSBs. It appears that this
specific synaptogenesis, rather than a net synaptogenesis,
supports successful learning of the trace eyeblink conditioned response
because the conditioning does not increase the total number of synapses
in the CA1 stratum radiatum (Geinisman et al., 2000).
MSB formation emerges as a general form of structural
synaptic plasticity
The results of the present work are in accord with those of
earlier studies showing that the addition of MSBs is associated with
motor skill learning (Federmeier et al., 1994; Jones et al., 1999).
These findings, taken together, indicate that various forms of learning
may promote MSB formation. Interestingly, this morphological alteration
is not unique to behavioral learning and related phenomena such as
hippocampal LTP (Toni et al., 1999) and an exposure to enriched
environments (Jones et al., 1997). The incidence of MSBs has been
reported to increase in various regions of the CNS under conditions
that induce plasticity: in the rat dentate gyrus for boutons of the
crossed temporodentate pathway after lesions of the ipsilateral
entorhinal cortex (Steward et al., 1988); in the rat hypothalamus as a
consequence of lactation, dehydration, or partial deafferentation (for
review, see Hatton, 1990); in the cat visual cortex after monocular
visual deprivation in the case of boutons on geniculocortical axons
that were driven from the nondeprived eye (Friedlander et al., 1991);
in the CA1 stratum radiatum of adult female rats after estradiol
treatment (Woolley et al., 1996); in the rat phrenic nucleus as a
result of an ipsilateral C2 spinal cord hemisection (Tai et al., 1997)
or a cold block of ipsilateral bulbospinal respiratory afferents
(CastroMoure and Goshgarian, 1997); in the rat motor cortex after
lesions of the contralateral sensorimotor cortex (Jones, 1999); in the
rat CA1 stratum radiatum after maintenance of living hippocampal slices in vitro (Kirov et al., 1999); and in the rat striatum after
an ablation of the ipsilateral frontal cortex (Meshul et al., 2000). These observations indicate that the formation of MSBs may represent a
general form of structural synaptic plasticity. The data of the present
study are consistent with this notion because they demonstrate that the
phenomenon of MSB formation is also characteristic of associative learning.
Functional implications of the formation of MSBs induced by
associative learning
The structural reorganization of synaptic connectivity that is
described here may have different functional implications, depending on
the origin of the postsynaptic spines contacting the newly formed MSBs
(Harris, 1995; Woolley et al., 1996; Jones et al., 1997). It has been
documented with the aid of three-dimensional reconstruction from serial
ultrathin sections that individual MSBs in the CA1 stratum radiatum can
synapse with spines arising from the same or different dendrites (Sorra
and Harris, 1993). However, an LTP-induced increase in the proportion
of activated boutons synapsing with two or more spines is essentially
caused by the formation of those MSBs that synapse with spines
originating from the same dendrite (Toni et al., 1999). In this study,
we were unable to reliably trace many multiple spines to their
dendritic origins and to obtain representative samples for quantitative analyses. It is not known, therefore, whether the MSBs that are newly
formed after trace eyeblink conditioning make synapses with spines
arising from the same dendrite. If this is the case, the strength of
the conditioned synaptic input to target CA1 neurons may be amplified.
If, however, the multiple postsynaptic spines synapsing with additional
MSBs emanate from dendrites of different neighboring neurons, this may
contribute to a synchronous activation of the latter and thus to the
assembly of functional multineuronal units tuned to the synaptic input
activated by conditioning stimulation. In either case, the effect of
conditioning stimulation would be facilitated, as it would be by the
learning-induced enlargement of nonperforated postsynaptic densities
that presumably reflects an addition of AMPA receptors (Geinisman et
al., 2000). It appears, therefore, that the conditioning may shape
synaptic drive via both MSB formation and postsynaptic density remodeling.
Models of structural plasticity underlying the formation of MSBs
after trace eyeblink conditioning
The addition of MSBs after hippocampus-dependent associative
learning may reflect the establishment of synaptic contacts between either newly formed or existing presynaptic and postsynaptic elements. This suggests three models of structural plasticity that may underlie MSB formation after trace eyeblink conditioning (Fig.
2). For the purpose of simplicity, the
following assumptions were incorporated into each model: (1) existing
single-synapse boutons are transformed into MSBs by the conditioning,
and (2) the spines that are postsynaptic to newly formed MSBs originate
from the same dendrite. The essence of the models, however, is not
affected by either assumption.
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Figure 2.
Models of structural plasticity underlying the
formation of multiple-synapse boutons after trace eyeblink
conditioning. A, Outgrowth of newly emerging spines for
specific synaptogenesis with single-synapse boutons activated by
conditioning stimulation. B, Coupling of the latter
process with the resorption of existing spines postsynaptic to
nonactivated boutons. C, Relocation of existing spines
from nonactivated boutons for specific synaptogenesis with activated
single-synapse boutons.
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According to the first model (Fig. 2A), conditioning
stimulation may induce the emergence of new spines and their outgrowth for a specific synaptogenesis with activated single-synapse boutons, probably in response to a signal emitted by the boutons. This model is
supported by the data that were obtained by labeling live CA1 pyramidal
neurons in cultured hippocampal slices with vital fluorescent markers
and time-lapse two-photon imaging of their spines (Engert and
Bonhoeffer, 1999; Maletic-Savatic et al., 1999). These experiments
demonstrated that spines and their structural precursors, termed
"dendritic filopodia," are constantly formed as well as resorbed
under normal conditions and that the process of new spine formation is
markedly augmented by local high-frequency stimulation of dendrites
that elicits LTP.
The second model (Fig. 2B) takes into account the
observation made in our previous study (Geinisman et al., 2000) that
the total number of axospinous synapses in the CA1 stratum radiatum is
not altered by trace eyeblink conditioning (group means ± SEM for
pseudoconditioned and conditioned rabbits were 22,851 ± 843 and
22,809 ± 911 synapses × 106,
respectively). On the basis of the data of the present work, it can be
estimated that the observed conditioning-induced increase in total MSB
number results on the average in the addition of 388 × 106 axospinous synapses that were formed
by MSBs in each conditioned animal. This would increase the mean total
number of axospinous synapses in the conditioned group by 1.7% as
compared with the pseudoconditioned group. Although such a trend may be
too small to be detected, it is also possible that the total number of
axospinous synaptic contacts actually remains constant in the
conditioned animals. In accordance with the latter possibility, the
second model postulates that the establishment of synaptic contacts
between newly formed spines and single-synapse boutons activated by
conditioning stimulation is accompanied by the resorption of some
postsynaptic spines contacting nonactivated boutons (Fig.
2B). In this case, some single-synapse boutons would
not form synaptic contacts. Such boutons without synapses are indeed
encountered in the CA1 stratum radiatum (Shepherd and Harris, 1998; our
unpublished observations),
Another model (Fig. 2C), which would not involve a change in
total synapse number, stems from the discovery of protrusive spine
motility (for review, see Halpain, 2000; Matus, 2000; Segal and
Andersen, 2000; Wong and Wong, 2000). A remarkable ability of spines to
rapidly elongate or retract in cultured hippocampal slices is
especially prominent during early postnatal development, but it is
retained to a certain degree after the maturation of CA1 pyramidal
neurons in slices obtained from developing animals and maintained in
culture (Dailey and Smith, 1996; Dunaevsky et al., 1999). Accordingly,
the third model posits that, after trace eyeblink conditioning, some
postsynaptic spines contacting nonactivated boutons leave their
presynaptic partners, relocate to boutons activated by conditioning
stimulation, and synapse with them (Fig. 2C).
Further studies are necessary to ascertain which of the three models
corresponds to reality. In any event, the data reported here provide
evidence that trace eyeblink conditioning promotes the formation of
MSBs. This process does not require a net synaptogenesis to take place;
rather, it reflects a specific synaptogenesis leading to an increase in
MSB number. The latter change translates into only a small (1.7%)
increase in the total number of all synapses in the CA1 stratum
radiatum, namely into an addition of 388 × 106 axospinous synapses to total synapse
number, which was estimated to be 23,267 × 106 in pseudoconditioned rabbits
(Geinisman et al., 2000). However, activation of no more than 3-5% of
all synapses in the CA1 stratum radiatum can evoke discharge from
virtually all CA1 pyramidal neurons (Andersen et al., 1980). The
structural alteration reported here is, therefore, of a magnitude that
appears to be sufficient for exerting a measurable facilitating effect
on the synaptic responsiveness of CA1 pyramidal cells to conditioning
stimulation. This would explain why a specific synaptogenesis resulting
in the formation of MSBs could underlie the acquisition of the trace eyeblink conditioned response.
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FOOTNOTES |
Received March 22, 2001; revised April 25, 2001; accepted May 18, 2001.
This work was supported by National Institutes of Health Grants NS34582
and AG17139 (Y.G.), and AG08796 (J.F.D.).
Correspondence should be addressed to Yuri Geinisman, Department of
Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. E-mail:
yurig{at}northwestern.edu.
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ABSTRACT
INTRODUCTION
