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Department of Psychology, The Neuroscience Program and The Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
Submitted 4 February 2003; accepted in final form 3 March 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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; Dunnett et al.
1988,
1990;
Mabry et al. 1996;
Martinez and Rigter 1983;
Oler and Markus 1998;
Winocur 1988;
Zornetzer et al. 1982). The
most pronounced memory deficit associated with age is typically the poor
retention of newly acquired information over time. This suggests that aged
animals are, to some extent, lacking the mechanisms required for the storage
and maintenance of new memories, but are not necessarily deficient in the
mechanisms necessary for the acquisition and initial formation of memories. A
number of studies have also shown impaired synaptic function in the
hippocampus of aged animals, possibly indicating that these changes may
underlay the poor learning performance in older animals
(Barnes 1994;
Geinisman et al. 1995;
Landfield 1988;
Thibault et al. 2001).
Long-term potentiation (LTP) of synaptic efficacy serves as the main
biological model for learning and memory processes in the CNS (for review, see
Bliss and Collingridge 1993).
The majority of studies are performed in young rats (<3 mo of age),
presumably because they provide a well-established animal model and possess a
large hippocampus, amenable to study both in vivo and in vitro (e.g., see
Blank et al. 2002;
Foster and Dumas 2001;
Ross and Soltesz 2001; Rush et
al. 2000). LTP in older animals has mainly been described in the medial
perforant path inputs to the dentate gyrus or the Schaeffer collateral inputs
of the CA1 region of the hippocampus proper. In these studies, it is primarily
the longevity of LTP that is compromised, not the initial posttetanic
magnitude (Barnes 1979,
1985; Deupree et al.
1991,
1993;
Landfield and Lynch 1977;
Landfield et al. 1978).
The more distal afferents of the entorhinal cortex into dentate gyrus (DG)
molecular layer can be both anatomically and functionally differentiated from
those of the medial perforant path
(Hjorth-Simonsen et al. 1972;
Steward 1976;
Wyss 1981) and have been shown
to support LTP in young animals both in vivo and in vitro (Chirstie and
Abraham 1992a; Colino and Malenka
1993; Hanse and Gustafsson
1992). There is growing evidence that processes more distal to the
soma may be more susceptible to age related reductions in receptor proteins
(Magnusson 1998) and intracellular elements
(Knapp and Klann 2002) that
can influence dendritic spine plasticity
(Gazzaley et al. 2002).
Currently, little is known as to how aging affects the distal processes of the
DG in mice, although this seems an important piece of knowledge given the fact
that genetic manipulations, including both transgenic and knock-out
procedures, are routinely performed in mice to examine synaptic plasticity or
aging. The present experiments examine the induction of synaptic plasticity in
the lateral perforant path input to the DG in vitro using mice ≤25 mo of
age.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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recording electrode filled with ACSF and a
Dagan BVC-700 amplifier. Responses were evoked with a sharpened tungsten
electrode (A-M systems) using biphasic current pulses (120 µs, 10–400
µA) and a digital stimulus isolation unit (Getting Instruments). All data
acquisition and analysis was performed using software provided by Getting
Instruments (Lee Campbell). An Olympus BX50wi microscope (10x objective) was used to visually position both the recording and stimulating electrodes for each experiment. Electrodes were positioned in the outer third of the molecular layer, adjacent to the hippocampal fissure, and distal from the dentate granule cell layer. Stimulation intensity was adjusted to yield response amplitudes approximately 30% of the maximum. All evoked responses were initially tested with paired-pulse stimuli (50-ms interpulse interval). During experiments, individual synaptic responses were continuously elicited at 15-s intervals, except during the application of the conditioning stimulation. After a minimum of 15 min of stable baseline responses were obtained, LTP was induced by applying four bursts of 50 pulses at 100 Hz (30 s between bursts). Single pulse stimulation was again initiated immediately following the last tetanus and continued for a minimum of 30 min. All data were acquired at 5–10 kHz, and the initial slope of the negative going waveform was used to assess changes in synaptic efficacy (Christie et al. 1999). Amplitude measurements were taken as the voltage difference between the initial 20 ms of data (acquired before presenting a stimulus), and the most negative component of the resulting stimulus induced waveform. Paired-pulse (PP) responses are presented as the normalized difference between the slopes of the two responses and are presented as a percentage change. LTP is quantified as the percentage change in individual responses collected following the application of conditioning stimuli compared with the average of 60 responses acquired prior to tetanic stimulation. In all figures, data are presented as the mean ± SE for that data set. For analysis purposes, data for unpaired t-tests were grouped according to whether the animal was older or younger than 12 mo of age.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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To determine whether there are age-related changes in the response profile
for lateral perforant path (LPP)-evoked responses, we evaluated the morphology
of evoked responses in mice 3–25 mo of age in vitro. Using a constant
intensity stimulus, we found that, overall, the size of the evoked response
elicited with LPP stimulation declined as a function of the age of the animal
[y = –0.1382x + 19.627, R2 =
0.046, F(1,121) = 23.8, P < 0.05;
Fig. 1A,
top). The difference in response size was not, however, due to
changes in any specific components of the response. Field EPSPs were similar
to those observed in young animals in previous in vitro studies
(Colino and Malenka 1993;
Hanse and Gustafsson 1992) in
all ages of animals examined here. As shown in
Fig. 1B, stimulation
of the LPP in both old and young animals elicited negative field EPSPs that
were identical in both latency and duration.
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Stimulation of the LPP has reliably been shown to result in PP facilitation
of responses recorded in the DG in young animals both in vivo and in vitro
(Christie and Abraham 1992a,b; Colino and
Malenka 1993; Hanse and
Gustafsson 1992; McNaughton
and Barnes 1977). Presumably this reflects a lower release
probability in lateral compared with medial perforant path synapses, further
differentiating the two inputs (McNaughton
and Barnes 1977; Zucker
1989). In animals up to 1 yr in age, application of the PP stimuli
to the LPP produced a significant PP facilitation in the DG (24.65 ±
2.4%, n = 47; t(46)= 10.05, P < 0.05;
Fig. 1C). Conversely,
in animals over 1 yr of age, the application of these same stimuli failed to
reliably produce a significant PP facilitation (6.74 ± 5.6, n
= 23; t(22)= 1.20, P > 0.05). All recordings
were visually confirmed as being in the outer molecular layer for both groups.
We next repeated these experiments with inhibition intact. Similarly, synapses
from animals less than 1 yr in age reliably exhibited PP facilitation (12.89
± 2.4, n = 42; t(41)= 5.38, P
< 0.05), while slices from animals older than 1 yr failed to exhibit
significant PP facilitation (3.20 ± 5.3, n = 8;
t(22)= 0.60, P > 0.05;
Fig. 2A). Taken
together, these data indicate that there may be differences in
neurotransmitter release that accompany the aging process, and that lateral
path synapses in older animals may have a higher probability of release.
Figure 1, C and
D, shows examples of PP responses recorded from both old
and young animals. Regression analysis of PP responses elicited in young and
old animals revealed that slices obtained from older animals exhibited
significantly less PP facilitation than did slices obtained from younger
animals (y = 0.0326x + 13.668, R2 =
0.0033, F(1,118) = 10.7, P < 0.05;
Fig. 1A,
bottom). To determine if the size of the initial evoked response may
have played a role in determining the degree of PP facilitation, regression
analysis was performed using the initial amplitude of the evoked response
across animals as the independent variable and the degree of PP facilitation
as the dependent variable. This analysis revealed that initial response
amplitude did not predict the degree of PP facilitation exhibited (P
> 0.05), confirming our previous observations in vivo (Christie and Abraham
1992a,b).
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Ability of the lateral perforant path to exhibit LTP declines with age
There is some controversy in the literature regarding the susceptibility of
the medial perforant path input to age-related declines in it's ability to
exhibit LTP. A number of studies have failed to find any age-related decrease
in the ability of the medial perforant path input to exhibit LTP, while others
have shown an age-related reduction in the ability of the medial perforant
pathway to sustain LTP (Barnes
1979; De Toledo-Morrell et al. 1988;
Landfield and Lynch 1977;
Maroun and Richter-Levin
2002). In normal ACSF, the application of high-frequency stimuli
(HFS) at 100 Hz for 0.5 s (repeated 4 times) to LPP fibers reliably elicited
robust short-term potentiation (STP; 15.0 ± 1.9%, n = 42;
t(41)= 7.98; P < 0.05) and LTP (13 ±
4%, n = 42; t(41)= 3.24; P < 0.05) in
animals <12 mo in age (see Fig.
2B). These findings are in agreement with previous work
examining the ability of lateral perforant path evoked responses to exhibit
LTP in younger animals (<3 mo; Colino and Malenka 1992;
Hanse and Gustafsson 1992). In
contrast, when we applied these same high-frequency stimuli to hippocampal
slices obtained from animals >12 mo in age, we did not observe significant
LTP. Although significant STP was observed in these slices (17.3 ±
3.3%, n = 42, t(41)= 5.3; P < 0.05),
this short-term effect did not translate into robust long-lasting LTP, and
moreover, a slight depression was observed (–9 ± 6%, n =
8, P > 0.05). Thus although there was no significant difference
between the amount of STP observed between slices obtained from animals
1–12 mo of age (15.0 ± 1.9%) or 12–25 mo of age (17.3
± 3.3%), slices obtained from older animals displayed significantly
less LTP than slices obtained from animals in the younger group
(t(48)=2.28, n = 49, P < 0.05).
Figure 3 illustrates these
findings and shows that for all animals tested, although STP is equivalent
across age (y = 0.031x + 20.755, R2 =
0.0032), LTP declines significantly as a function of age (y =
–0.1382x + 19.627, R2 = 0.046).
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Blocking GABAA-mediated inhibition facilitates synaptic plasticity in young, but not old, animals
As the level of synaptic inhibition changes with age
(DiScenna and Teyler 1994), we
tested the effects of blocking GABAA inhibition in slices obtained
from old and young animals by adding 1.0 µM bicuculline to the perfusion
medium. This procedure is routinely used to aid in the induction of LTP of
medial path evoked responses in vitro, presumably by aiding in the spread of
depolarization into the dendrites being stimulated (Colino and Malenka 1992;
Sloviter and Brisman 1995;
Tomasulo et al. 1993;
Wang and Wojtowicz 1997;
White et al. 1990). There was
a small, but nonsignificant, increase in the amount of STP observed in slices
taken from older animals (>12 mo) compared with that observed in normal
ACSF (Bicuc: 28.3 ± 5.0%; Normal: 17.3 ± 3.2%). Surprisingly,
this effect was greater in slices obtained from young animals, where STP
increased significantly from 15.0 ± 1.8% to 27.7 ± 3.2%
(t(87)3.30; n = 88, P < 0.05,
Fig. 4). As was observed in
normal ACSF, slices from young animals (<12 mo) exhibited significant LTP
(t(68)=2.24; n = 69, P < 0.05; 16.0
± 3.0%). Slices taken from older animals also showed significantly more
STP in the presence of bicuculline (29.6 ± 5.0%); however,
significantly less LTP was still observed in these slices (4.4 ± 4.2%;
t(68)= 2.24; n = 69, P < 0.05) than
in those taken from younger animals.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The present results demonstrate that the lateral perforant path input to the DG exhibits numerous changes that manifest themselves in electrophysiological indices of synaptic plasticity. First, although responses evoked with LPP stimulation did not differ morphologically, they did tend to be of smaller amplitude in older animals. This may reflect either a change in the number of postsynaptic spines present on granule cell dendrites; the number or density of postsynaptic receptors, and/or their respective subtypes; some alteration in the release properties of presynaptic fibers; or a combination of any of these pre- and postsynaptic changes.
We next used PP facilitation to examine whether changes occurred in presynaptic release properties. Although there is still some disagreement in the literature as to whether, or to what extent, hippocampal synapses change during aging, our examinations did reveal that PP facilitation can change in the LPP as a function of age. Because a similar decrease was observed whether or not bicuculline was added to the ACSF, it appears that synapses in the outer portion of the molecular layer have a higher probability of release in older animals. It is interesting to note that this finding suggests that the decrease in response size we observed in aged animals is not due to a reduction in presynaptic release properties. However, further testing is required to discern whether the observed reduction in PPF is due to some structural/functional change that occurs in existing lateral path inputs in this region, or whether there might be some age-related infiltration of medial path synapses into this region in older animals.
Another major finding of this study was that LTP of synaptic efficacy was
significantly decreased in lateral path synapses in older animals. STP was
reliably produced in both young and old animals, suggesting that the synaptic
mechanisms activated by the conditioning stimuli were intact, regardless of
age. However, STP was only reliably translated into LTP in slices obtained
from animals <1 yr in age, indicating that synapses in older animals are
not as plastic as those of their younger counterparts. This deficiency was not
the result of differences in the initial size of the evoked response or due to
alterations in levels of inhibition in these animals. As part of the LTP
induction protocol, all animals were tested using stimulus intensities that
elicited responses approximately 30% of maximal amplitude. At this intensity,
there was no significant difference in the initial response size between young
and old animals. Similarly, addition of bicuculline to the bathing medium did
not alter response sizes in either young or old animals. Slices taken from
young animals showed a similar degree of LTP whether bicuculline was present
(16 ± 3.0%) or absent (13 ± 4.0%). In the case of older animals,
no significant change in the initial slope of the EPSP was observed whether
bicuculline was present or absent. Taken together, these data support the
conclusion that the ability of the lateral perforant path to exhibit changes
in synaptic efficacy declines with age, independent of changes in
GABAA-mediated inhibition. In studies involving responses elicited
by stimulation of the medial perforant path, there is some evidence that
putative "mature" cells may require GABAA-mediated
inhibition to be blocked for them to exhibit LTP
(Wang et al. 2000). In this
study, "mature" neurons were differentiated from
"young" neurons based on a number of morphological criteria, and
it was proposed that the "young" neurons resulted from the process
of neurogenesis and had different physiological properties compared with more
mature neurons. Wang et al.
(2000) further showed that
cells that were putatively identified as "young" neurons were
unaffected by the addition of bicuculline to the bathing medium. It may be
that lateral perforant path stimulation preferentially activates these
"young" neurons, but that under normal circumstances their numbers
are insufficient in older animals to sustain LTP of field responses
normally.
Mechanisms of age-related LTP deficits
Another difference between this and other studies examining age-related
deficits in LTP is the fact that these differences are observed following
HFS-induced LTP. Studies in CA1 have shown that age-related deficits in the
expression of LTP are evident when LTP is induced with physiologically
patterned stimulation, but that they are obscured when HFS is used
(Barnes et al. 1996;
Chang et al. 1991;
Deupree et al. 1993;
Landfield et al. 1978;
Moore et al. 1993;
Norris et al. 1996). Moreover,
it has been suggested that patterns of stimulation that are more
physiologically relevant than conventional HFS paradigms are required to
accurately assess the ability of the hippocampus for encoding information
(Moore et al. 1993). This does
not seem to be the case with lateral perforant path synapses given the present
results. In addition, there is widening support that the HFS stimulation
protocol is also physiologically relevant. First, increases in postsynaptic
intracellular Ca2+ concentrations have been associated
with high-frequency patterns of stimulation
(Jager et al. 2002). Second,
gamma oscillations (30–100 Hz) are known to be evoked by bursts of LTP
inducing bursts of HFS (100 Hz) (Poschel
et al. 2003) and by sensory stimulation
(Poschel et al. 2002).
Finally, frequencies in this range are also thought to play a role in binding
sensory information (Gray et al.
1989), the formation of short-term memories
(Lisman and Idiart 1995), and
to be important for synchronizing the activity of local and anatomically
distributed populations of neurons (Buzsaki
and Chrobak 1995).
Although our study did not investigate whether changes in receptor
populations were responsible for the decrease in LTP observed, Clayton et al.
(2002) have reported
age-related (6 vs. 16–24 mo) decreases in hippocampal NR1 and NR2B
subunits of the NMDA receptor. They have also shown that decreased NR2B levels
are correlated with reduced LTP and spatial ability in the Morris water-maze.
In contrast, mice overexpressing the NR2B subunit show enhanced LTP effects,
improved object recognition, and heightened contextual fear conditioning
(Tang et al. 1999). In
addition, Magnusson et al. (2002) have recently shown that NR2B mRNA levels
decline as a function of age in C57BL/6 mice like those used here, supporting
the hypothesis that an age-related decrease in NR2B expression may underlie
the reduction in LTP expressed in aged animals.
Clayton et al. (2002) have
suggested that increased concentrations of calcium associated with age may be
the cause of the selective down-regulation of NR2B levels. Age-related
increases in cytosolic Ca2+ levels can result from
altered calcium homeostasis (Thibault et
al. 1998) and increased activity at voltage-gated calcium channels
(Thibault and Landfield 1996).
Thus the age-associated reduction of LTP may reflect an increase in cytosolic
Ca2+ and shift the kinase-phosphatase balance to
facilitate long-term depression (LTD) and impair LTP
(Foster 1999). In partial
support of this theory, overexpression of CaN in young rats has been shown to
produce similar impairments of synaptic plasticity
(Mansuy et al. 1998;
Mayford and Kandel 1999;
Winder et al. 1998;
Zhuo et al. 1999). According
to this hypothesis, LTD should be easier to induce in older animals owing to
the fact that protein dephosphorylation is a critical component of long-term
decrements in synaptic efficacy. In hippocampal CA1 in vitro, both LTD and
depotentiation, the reversal of previously established LTP, were, in fact,
shown to be greater in magnitude in aged compared with adult Fischer 344 rats,
but this difference was attributed to an age-dependent alteration in
Ca2+ regulation
(Norris et al. 1996).
Furthermore, this facilitation of LTD induction and impairment of LTP
induction in aged rats could be reversed by L-type Ca2+
channel blockade (Norris et al.
1998). It is interesting that in our preparation, high-frequency
stimulation actually induced a modest depression in aged animals, rather than
LTP, giving some credence to this hypothesis.
While altered synaptic function in hippocampal circuits has been associated
with age-related learning and memory deficits
(Barnes 1994;
Foster and Norris 1997),
little is known about age-related alterations in LTP in the dentate gyrus or
the behavioral implications of such changes. Lesions of the lateral entorhinal
cortex have been shown to prolong the duration of recognition memory on
olfactory tasks (Ferry et al.
1996; Wirth et al.
1998). Thus the lateral path input to the dentate gyrus is an
integral part of a normal functioning hippocampal circuit, and our research
indicates that it may play a key role in age-related changes in synaptic
plasticity and learning and memory. This research represents an important step
in elucidating the mechanisms underlying age-related declines in learning and
memory functions by indicating that there may be structural or mechanistic
changes in the integrity of the mammalian dentate gyrus across the life span.
Furthermore, this research suggests that such age-related deficits may be
apparent first in the more distal processes of DG cells.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This research was funded by grants to the British Research Council from the Canadian Institutes for Health Research, the Natural Sciences and Engineering Research Council of Canada, The Canadian Foundation for Innovation, and the Human Early Learning Partnership (British Columbia Ministry of Children and Development).
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FOOTNOTES |
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* These authors contributed equally to this work. 
Address for reprint requests: B. R. Christie, Dept. of Psychology, The Neuroscience Program and The Brain Research Centre, Univ. of British Columbia, 2136 West Mall, Vancouver, British Columbia V6T 1Z4, Canada (E-mail: bchristie{at}psych.ubc.ca).
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