1Department of Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-6209; and 2Department of Biological Sciences, Stanford University, Stanford, California 94305-5020
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ABSTRACT |
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Foster, T. C. and T. C. Dumas. Mechanism for Increased Hippocampal Synaptic Strength Following Differential Experience. J. Neurophysiol. 85: 1377-1383, 2001. Exposure to novel environments or behavioral training is associated with increased strength at hippocampal synapses. The present study employed quantal analysis techniques to examine the mechanism supporting changes in synaptic transmission that occur following differential behavioral experience. Measures of CA1 synaptic strength were obtained from hippocampal slices of rats exposed to novel environments or maintained in individual cages. The input/output (I/O) curve of extracellularly recorded population excitatory postsynaptic potentials (EPSPs) increased for animals exposed to enrichment. The amplitude of the synaptic response of the field potential was related to the fiber potential amplitude and the paired-pulse ratio, however, these measures were not altered by differential experience. Estimates of biophysical parameters of transmission were determined for intracellularly recorded unitary responses of CA1 pyramidal cells. Enrichment was associated with an increase in the mean unitary synaptic response, an increase in quantal size, and a trend for decreased input resistance and reduction in the stimulation threshold to elicit a unitary response. Paired-pulse facilitation, the percent of response failures, coefficient of variance, and estimates of quantal content were not altered by experience but correlated well with the mean unitary response amplitude. The results suggest that baseline synaptic strength is determined, to a large extent, by presynaptic release mechanisms. However, increased synaptic transmission following environmental enrichment is likely due to an increase in the number or efficacy of receptors at some synapses and the emergence of functional synaptic contacts between previously unconnected CA3 and CA1 cells.
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INTRODUCTION |
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It is believed that cognitive
ability is a function of the dynamics of synaptic connectivity between
neurons, and memory operations may depend on adjustments in synaptic
transmission properties due to the history of synaptic activity
(Foster 1999). Notable advances have been made in
identifying and characterizing two forms of activity-dependent synaptic
plasticity, long-term potentiation and long-term depression (LTP and
LTD), which are manifest following patterned activation of neural
circuits (Bliss and Collingridge 1993
). However,
information on endogenous mechanisms for naturally occurring changes in
synaptic strength with experience is still lacking.
Differential experience (e.g., exposure to enriched or novel
environments) influences hippocampal anatomy, physiology, and biochemistry. Relative to "normal" laboratory animals, an increase in hippocampal synaptic efficacy is observed in vitro following exposure to novel environments or behavioral conditioning
(Foster et al. 1996; Green and Greenough
1986
; Power et al. 1997
). The observation of
increased synaptic transmission recorded in vitro indicates that
synaptic changes are long-lasting and expression is not due to
extrahippocamal systems involved in arousal. Thus experience-dependent
growth in synaptic strength is preserved in the hippocampal slice
providing an opportunity to examine the mechanisms for expression of a
naturally occurring change in synaptic function.
Statistical analysis of the fluctuations in unitary responses can be
used to provide estimates of biophysical parameters of transmission.
These techniques have been used to explore the mechanisms for
endogenous changes in CA3-CA1 synaptic function across the life span
(Barnes et al. 1992; Dumas and Foster
1995
; Hsia et al. 1998
). Therefore as a starting
point for examination of potential mechanisms for expression of the
experience-dependent increase in synaptic transmission, we examined
unitary responses recorded from pyramidal cells in region CA1 of
control animals and animals exposed to environmental enrichment.
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METHODS |
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Sprague-Dawley rats were bred and housed in our vivarium and maintained on a reversed 12:12 h light/dark cycle. On postnatal day 1 (P1), litters were restricted to a maximum of 10 pups with no less than 2 female pups per litter. Males were separated from females and weaned on P21. At P42, rats were randomly assigned to individual cages (IC) or enriched conditions (EC). Animals in the IC group were individually housed in wire cages (25 × 18 × 21 cm) and only handled for routine upkeep. Each day, EC rats (2-3 per cage) were taken from the home cage (25 × 18 × 66 cm) and placed for 1-6 h in a novel environment (e.g., empty water maze, large wooden box, or large wire cage) that contained three-dimensional objects (e.g., coffee cans, children's plastic toys, cardboard boxes, large plastic drain pipes), rat chow, and a water bottle. The exposure to each environment and three-dimensional objects was nonsystematically randomized across days. Following 25-32 days of differential experience (i.e., P67-74), animals were deeply anesthetized, their hippocampi were harvested, and hippocampal slices (450-500 µm) were cut parallel to the alvear fibers. Slices were then transferred to a standard recording chamber, and perfused at 32°C with oxygenated artificial cerebrospinal fluid (ACSF) containing the following (in mM): 124 NaCl, 2 KCl, 1.25 KH2PO4, 2 MgSO4, 2 CaCl2, 26 NaHCO3, and 10 glucose. Humidified air (95% O2-5% CO2) was continuously blown over the slices.
Extracellular recording
Extracellular field potentials were recorded with ACSF-filled
glass micropipettes (4-6 M). The recording and stimulating electrodes were separated by ~1 mm and localized to the middle of the
s. radiatum. The signals were amplified, filtered (1 Hz to 1 kHz), and
stored on computer disk for off-line analysis. The viability of the
slices was examined, and only those slices exhibiting a field potential
synaptic response of at least 1.5 mV for 200 µA stimulation were
employed for further analysis. Biphasic constant current stimuli (100 µs) were delivered such that paired stimulation pulses (50-ms
interstimulus interval) occurred once every 30 s. The paired-pulse
ratio of the field potential synaptic responses was calculated as the
quotient of the response to the test pulse divided by the response to
the conditioning pulse. Input/output (I/O) curves of the field
potentials were constructed using the means of five conditioning
stimulus pulses at three stimulation intensities (100, 200, and 300 µA). In addition, I/O curves were constructed across seven levels
based on the fiber potential amplitude. The seven levels were chosen to
ensure that ~15 of the total responses were included at each level.
For induction of LTP, the stimulation intensity was set to elicit
excitatory postsynaptic potential (EPSP) of ~1 mV. Following 20-30
min of stable baseline recording (0.033 Hz), LTP was induced (2 1-s
bursts of 100 Hz, each burst separated by 10 s), and recording continued for another 30 min.
Intracellular recording and quantal analysis
Methods for collection of unitary responses and quantal analysis
have previously been published in detail (Dumas and Foster 1995; Foster and McNaughton 1991
). Briefly,
intracellular responses were obtained using glass micropipettes (50-90
M
) filled with 3 M K+-acetate. Only cells that
exhibited a resting membrane potential of
60 mV or below, a spike of
at least 60 mV greater than the excitatory synaptic potential, and an
input resistance >20 M
were considered suitable. The membrane
potential was held at or near
72 mV (using less than ±0.2 nA).
Synaptic responses were elicited by biphasic minimal-stimulation (100 µs, 5-80 µA) and consisted of paired pulses of identical
intensity, separated by 50 ms, with one such pulse pair delivered every
5 s. Once a cell had met the criteria for recording, the
stimulation intensity was lowered such that the smallest consistent
averaged response was obtained. At this intensity, transmission
failures were apparent and interspersed among responses that appeared
to fluctuate in discreet steps (see Fig. 5). Responses to the
conditioning stimulation were averaged on-line to ensure response
stability. If the average response amplitude tended to increase or
decrease over blocks of 50 trials, recording was continued until a
stable response was obtained for at least 150 trials (294 ± 12 mean number of trials, mean ± SE). Stimulus timing and data
collection were computer controlled, and data were stored on computer
as 50-ms records (2 ms of baseline and 48 ms after stimulation).
Background system noise records were collected just prior to
conditioning stimulation for each trial. Response amplitudes were
calculated as the difference between the membrane potential averaged
with in a 1- to 2-ms window just prior to stimulus onset and a similar
window centered over the peak of the evoked response. This procedure of
obtaining the average potential difference between two discreet time
windows was then performed on the noise-only records to estimate the
noise contribution to the EPSP measurements.
Several independent methods were employed to examine the biophysical
mechanisms of synaptic transmission. First, the number of transmission
failures (n0) was estimated as two
times the number of responses less than zero plus those that were equal
to zero. The number of failures was used to estimate the percent of
transmission failures (n0/total number
of responses). Six cells were not included in the analysis due to
transmission failures beyond the range of >5 or <0.95% of the total
number of responses for the conditioning stimulation. Our previous
experience indicates that estimates of biophysical parameters become
unreliable for responses beyond this range (Foster and
McNaughton 1991). Second, the coefficient of variation (CV) was
calculated according to the equation: CV =
/M, where
M is the mean EPSP amplitude, and
is the standard deviation of the response minus the standard deviation of the noise-only records. Third, to estimate quantal parameters, noise deconvolution and parameter optimization analyses were applied under
assumptions of Poisson (m, q) release
(Dumas and Foster 1995
; Foster and McNaughton
1991
). Response amplitudes were divided into 30 bins, and the
parameters of best fit were determined by comparing the observed
distribution with a distribution generated for Poisson release
parameters and convolved with the noise distribution. The parameter
values were altered according to a nonlinear optimization routine. The
algorithm was constrained to positive values for all variables and the
best fit determined by a
2 test. As a final
method, the data were subjected to a computer optimization algorithm
that compares the entropy (i.e., smoothness or flatness) and detection
of peaks in the response distribution (i.e., maximum entropy noise
deconvolution, MEND) (Kullmann 1992
). The MEND analysis
enables the detection of peaks and makes no assumption concerning the
underlying transmission mechanisms. In this case, when peaks are
detected, the distance between peaks provides an estimate of quantal size.
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RESULTS |
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Extracellular recording
To establish that transmission at CA3-CA1 synapses was altered by the environmental enrichment procedure, I/O curves were constructed using three stimulus levels. In cases where recordings were taken from more than one slice from the same animal, the responses within each level were averaged. Figure 1 illustrates that the fiber potential amplitude (Fig. 1A) and paired-pulse ratio (Fig. 1B) were not different between EC (n = 15) and IC animals (n = 15) across the three stimulus intensities of the I/O curve. In contrast the field potential synaptic response was increased across the I/O curve [F(1, 56) = 4.2, P < 0.05]. Figure 1D shows the EPSP slope plotted against fiber potential amplitude across the 50 individual slices (EC, n = 23; IC, n = 27). In this case, the responses at each level of the I/O curve were assigned to one of seven groups according to the fiber potential amplitude (Fig. 1C). An ANOVA on the EPSP slope across the seven fiber potential levels confirmed a significant increase in synaptic strength for responses elicited from slices of EC animals [F(1, 137) = 27.73, P < 0.0001].
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While difference in synaptic efficacy due to experience was not related to changes in the fiber potential amplitude and paired-pulse ratio, the measures correlated with the overall level of synaptic strength and much of the variability in the response could be accounted for by these factors. The slope of the population synaptic response of the field potential was positively correlated with the fiber potential at each level of the I/O curve (300 µA: R2 = 0.29, P < 0.005; 200 µA: R2 = 0.43, P < 0.0001; 100 µA: R2 = 0.52, P < 0.0001). Further, the paired-pulse ratio was inversely correlated with the field potential synaptic response at 200 µA (R2 = 0.36, P < 0.0005) and 100 µA (R2 = 0.27, P < 0.005). In contrast, the treatment condition accounted for <15% of the variability in the population synaptic response at each stimulus level (300 µA: R2 = 0.12, P = 0.06; 200 µA: R2 = 0.11, P = 0.08; 100 µA: R2 = 0.14, P < 0.05).
For some slices, the stimulation intensity was set to elicit a 1-mV field potential synaptic response, and, after collection of the baseline responses, LTP was induced (Fig. 2). An examination of the slope of the field potential synaptic response 30 min after LTP induction indicated a significant increase in the synaptic response for slices from EC (n = 12; 164 ± 16%) and IC rats (n = 13; 149 ± 8%) with no difference between groups.
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Intracellular recording of unitary responses
Acceptable intracellular recordings were obtained from 32 and 31 cells from EC and IC animals, respectively. Table
1 combines the data from the two groups
and summarizes the results comparing transmission characteristics for
the conditioning and test pulses of paired-pulse stimulation.
Paired-pulse stimulation resulted in an increase in the test response
[F(1, 62) = 44.62, P < 0.0001]. Facilitation is thought to result from an increase in the probability of transmitter release such that the percent of transmission failures is reduced for the test pulse compared with the conditioning pulse (Fig. 3). As predicted, the percent of
transmission failures decreased for the test pulse [F(1,
62) = 41.60, P < 0.0001], consistent with the
notion that the increase in synaptic strength is due to an increase in
transmitter release. The coefficient of variance was observed to
decrease [F(1, 62) = 35.06, P < 0.0001], which again is consistent with an increase in presynaptic
function (Korn and Faber 1991). Finally, nonlinear
parameter optimization using noise deconvolution indicated an increase
in quantal content [F(1, 62) = 29.49, P < 0.0001] for the test response, in the absence of
a change in quantal size (Table 1). Together, the results indicate that
the techniques can detect a change in synaptic strength due to an
increase in transmitter release.
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Table 2 shows the means for intracellular recording parameters and waveform characteristics of the averaged unitary responses for the two treatment groups. Comparison of the mean EPSP amplitude for unitary responses across the two experience conditions indicated a significant effect of experience [F(1, 61) = 3.98, P < 0.05], with the EC group exhibiting an increase in the mean unitary response (Fig. 4A). Due to the fact that the EPSP amplitude was increased for the EC group, comparison of biophysical parameters was performed using one-tailed Student's t-tests. No difference was observed for any of the waveform characteristics of the averaged unitary synaptic responses (10-90% rise time, half-width, time-to-peak), suggesting that synaptic responses were generated at similar locations along the dendrite. In addition, no difference was observed for the resting membrane potential and action potential amplitude. The paired-pulse ratio was not different between groups, suggesting that the increase in synaptic strength for the EC group was not due to a change in the probability of transmitter release. There was a tendency (P = 0.07) for the input resistance to decrease for cells from animals exposed to enrichment and for greater stimulation intensity to elicit unitary responses from cells of the IC group (P = 0.06; Fig. 4B).
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The increase in the EPSP for the EC group was not associated with a
change in the percent of transmission failures (Table 3). Furthermore, the coefficient of
variance was not different between groups. A change in synaptic
strength, in the absence of a change in the coefficient of variance,
suggests that quantal size is altered (Korn and Faber
1991). Results of the optimization procedure indicated a
significant increase in quantal size [t(61) = 1.79, P < 0.05] and an increase in the signal-to-noise
ratio [t(61) = 1.80, P < 0.05]
(Table 3).
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The noise deconvolution procedure makes assumptions about the
distribution of responses (i.e., Poisson release), which may influence
the results. Therefore the data were fit (P < 0.05) using a procedure that makes no assumption about the release process or
the distance between the response amplitudes (Kullmann
1992). However, this technique requires a larger number of
samples. Therefore the MEND procedure was employed only in cases in
which at least 450 responses were recorded from the cell (EC:
n = 9; IC: n = 10). For individual
cells, the number of peaks that had a probability of occurrence of
>5%, and were one noise standard deviation above 0 mV, ranged from 1 to 7 (3.53 ± 0.38, mean ± SE) and did not differ between
the two groups (Table 3). Across all cells, variability in the distance
between the peaks was ~16% of the mean distance between the peaks.
Finally, the mean distance between the peaks was greater for the EC
group [t(18) 2.48, P < 0.05], consistent with the idea that the increase in the EPSP amplitude for EC animals is
associated with an increase in quantal size. Figure
5 provides an example of a cell from an
EC animal, with a large signal-to-noise ratio and apparent quantal
transmission.
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Regression analyses indicated that mean unitary responses were not correlated with intracellular recording parameters, waveform characteristics, or stimulation intensity. The experience condition accounted for only 10% of the variability in averaged unitary response amplitude (R2 = 0.10, P < 0.01) and, for 19 cells in which estimates were obtained by MEND analysis, quantal size accounted for <30% of the EPSP variability (R2 = 0.28, P < 0.05). In contrast, approximately one-half of the variability in the mean synaptic responses could be explained by variability in release parameters including the percent of transmission failures (R2 = 0.49, P < 0.0001), coefficient of variance (R2 = 0.48, P < 0.0001), and mean quantal content estimated by nonlinear parameter optimization involving noise deconvolution (R2 = 0.40, P < 0.0001; Fig. 6). In addition, the mean EPSP amplitude was negatively correlated with the paired-pulse ratio across all cells (R2 = 0.29, P < 0.0001).
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DISCUSSION |
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Effects of environmental enrichment on synaptic function
This study demonstrates that, following environmental enrichment,
an increase in CA3-CA1 synaptic strength can be observed in vitro. A
naturally occurring increase in synaptic strength associated with
environmental enrichment has previously been described for perforant
path synapses of the dentate gyrus (Foster et al. 1996,
2000
; Green and Greenough 1986
). The
enrichment-dependent increase in perforant path synaptic strength is
mediated by increased
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptor function and interacts with mechanisms for LTP.
Previous research indicates that, like perforant path LTP, CA3-CA1 LTP
induction is impaired shortly after an initial exposure to a novel
environment or stressful situation (Garcia et al. 1997
;
Waters et al. 1997
; Xu et al. 1997
).
Interestingly, the current study found that, in contrast to perforant
path synapses, LTP could still be induced at CA3-CA1 synapses 24 h
after the final exposure to novel environments. One possible
explanation for regional and temporal differences is that the effects
of enrichment may be more persistent in the dentate gyrus. For example,
increased AMPA receptor binding is more enduring in the dentate gyrus
(Cammarota et al. 1996
). Alternatively, dentate granule
cells and CA1 pyramidal cells may exhibit differential growth of new
spines due to enrichment (Juraska et al. 1985
;
Moser et al. 1994
). The emergence of new spines in CA1
might reflect new synapses that retain the potential to undergo
subsequent LTP (Engert and Bonhoeffer 1999
). Regardless,
the results indicate that the mechanisms for LTP induction are
differentially regulated by experience in the two regions.
Presynaptic and postsynaptic contributions
to synaptic strength
Recent controversies concerning presynaptic and postsynaptic
contribution to synaptic plasticity have raised questions concerning the limitations of quantal analysis methods and validity of the parameter estimates. In many cases, the source of the differences can
be traced to differences in experimental techniques (e.g., developmental state, temperature), the method for data selection, and
inappropriate assumptions concerning the quantal analysis techniques
(Korn and Faber 1991; McNaughton and Foster
1990
; Redman 1990
). The frequency of synaptic
transmission failures and consequent estimates of quantal content
provide classic measures of presynaptic function (del Castillo
and Katz 1954
). However, for central synapses, it is unclear
whether a change in failure rate is due to altered probability of
release or the number of transmission sites. Furthermore, the
coefficient of variation is also influenced by variance in quantal size
(Faber and Korn 1991
). As Korn and Faber
(1991)
have pointed out, in the case of altered synaptic
transmission, the only unequivocal conclusion is that quantal size is
altered when the coefficient is unchanged as was observed in the
current study. To provide valid estimates of quantal size, various
deconvolution procedures have been devised. While noise deconvolution
under constraints of Poisson release appear to adequately describe
release at CA3-CA1 synapses of adults (Foster and McNaughton
1991
; Sayer et al. 1990
) and hippocampal
cultures (Bekkers and Stevens 1995
), constrained
parameter optimization may over fit the data. This has led to the
development of deconvolution procedures that do not make any assumption
about the release model (Edwards et al. 1976
;
Kullmann 1992
). However, estimates of quantal parameters according to unconstrained deconvolution are still limited by the
sample size and background noise. Thus the limitations and assumptions
of any single parameter extraction technique will determine the utility
of that technique for quantal analysis.
The current study utilized a number of parallel techniques to reduce
the reliance on assumptions underlying any single technique. The
strongest support for the validity of the techniques is that the
expected results were obtained for paired-pulse facilitation, for which
an extensive literature indicates an increase in presynaptic function
(Debanne et al. 1996; del Castillo and Katz
1954
; Foster and McNaughton 1991
; Hess et
al. 1987
). Quantal content was similar to that previously
observed for synaptically connected cell pairs in adult rats
(Foster and McNaughton 1991
; Sayer et al.
1990
), indicating that one or very few fibers were activated by
the minimal stimulation. The mean unitary response amplitude for the
conditioning pulse was inversely related to the paired-pulse ratio, the
level of transmission failures, and coefficient of variance and was positively correlated with mean quantal content estimated by the nonlinear parameter optimization using noise deconvolution. The finding
that presynaptic function accounts for most of the variability in
synaptic strength is a consistent finding and is likely due to the
large variability in mean quantal content compared with quantal size
(Dumas and Foster 1995
; Foster and McNaughton
1991
; Markram et al. 1997
). The strong
relationship between mean quantal content and the synaptic response
emphasizes the importance of this biophysical parameter in determining
baseline synaptic strength.
Although presynaptic function is the major determinant of synaptic
strength, changes in transmitter release are not responsible for the
increase in synaptic strength due to experience. Despite the increase
in synaptic strength for the EC animals, all measures of presynaptic
function including the failure rate, coefficient of variance, quantal
content, and the paired-pulse ratio were not altered by differential
experience. The increase in synaptic strength, in the absence of a
change in the coefficient of variation, provides strong evidence of an
increase in quantal size (Korn and Faber 1991). This
conclusion is supported by the results from the two noise deconvolution
procedures that indicate that the increase in synaptic strength
associated with differential experience is due to an increase in
quantal size. Thus while quantal size contributed less to overall
variability in synaptic strength, increased quantal size was observed
in animals exposed to enrichment conditions.
It is unclear what mechanism underlies the increase in quantal size;
however, experience-dependent enhancement of synaptic strength is
associated with an increase in AMPA receptor binding, suggesting
increased affinity or number of receptors at preexisting synapses
(Foster et al. 1996; Gagne et al. 1998
)
resulting in increased postsynaptic responsiveness to transmitter. In
addition, increased AMPA binding may represent new transmission sites
that arise through the unmasking of postsynaptic receptors at
previously "silent" synapses or the growth of new synaptic
contacts. The absence of a change in quantal content or the MEND
analysis estimate of the number of transmission sites (i.e.,
n) suggests that the growth in synaptic strength was not due
to the addition of more transmission sites between connected CA3-CA1
cell pairs. It is possible that differential experience was associated
with divergence of synaptic contacts and the appearance of new
transmission sites between cells that previously lacked functional
connections. The tendency for reduced input resistance in the EC group
is consistent with reports of an increase in spine density
(Moser et al. 1994
). The reduction in input resistance
is not likely due to an increase in the spontaneous release of
transmitter (e.g., GABA) since no difference was observed in the
standard deviation of the noise-only records. Furthermore, a decrease
in the stimulation intensity needed to activate a unitary response is
consistent with an increased likelihood of a synaptic contact between
individual CA3 fibers and the population of CA1 cells.
The results do not limit other mechanisms for naturally occurring
changes in synaptic strength due to experience. The diversity of
conclusions for quantal analysis of LTP indicate that the manifestation of distinct pre- or postsynaptic mechanisms depends on a number of
relevant variables including developmental state and initial transmission parameters (Durand et al. 1996;
Larkman et al. 1992
; McNaughton and Foster
1990
; McNaughton et al. 1994
; Williams et al. 1993
). For example, several laboratories have recently
provided evidence that the increase in quantal content observed
following LTP in the developing neonatal hippocampus may be due to
postsynaptic mechanisms involving the unmasking of silent synapses
(Durand et al. 1996
; Isaac et al. 1995
;
Liao et al. 1995
). It will be important for future
studies to determine whether the new transmission sites represent an
increase in the control of previously connected and communicating
CA3-CA1 neurons or an increase the divergence of CA3 synaptic contacts
with the population CA1 cells. Finally, it may be significant that LTP
in CA1 of hippocampal slices from adults is associated with an increase
in quantal size (Foster and McNaughton 1991
). This
initial discovery for a major role of quantal size in expression of LTP
has been confirmed by a number of different investigators
(Cormier and Kelly 1996
; Isaac et al. 1998
; Kullmann and Nicoll 1992
; Liao et
al. 1992
; Manabe et al. 1992
; Stricker et
al. 1999
). These results suggest that
N-methyl-D-aspartate (NMDA) receptor-dependent
mechanisms may underlie the increase in synaptic strength associated
with differential experience (Foster et al. 2000
), while
regulation of presynaptic function may depend on other physiological or
behavioral processes (McNaughton et al. 1994
;
Stricker et al. 1999
). Alternatively, activity-dependent release of neurotrophic factors can increase quantal size and influence
synaptic connectivity (Sherwood and Lo 1999
;
Thoenen 1995
). Regardless of the mechanism, the results
suggest that postsynaptic alterations are important for the maintenance
of a stable increase in synaptic strength associated with differential experience.
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ACKNOWLEDGMENTS |
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Special thanks go to K. Sharrow and J. Masse for help in preparing the manuscript.
This research was supported in part by National Institutes of Health Grant AG/NS-14979 and National Science Foundation Grant IBN-97230055.
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FOOTNOTES |
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Address for reprint requests: T. C. Foster (E-mail: Tfoster{at}pop.uky.edu).
Received 19 September 2000; accepted in final form 21 December 2000.
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REFERENCES |
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