Frontiers in Aging Neuroscience www.frontiersin.org February 2010 | Volume 2 | Article 1 | 1
published: 05 February 2010
impaired in aged rodents (Barnes et al., 1997; Potier et al., 2000), the
mechanisms that signifi cantly contribute to this alteration have yet to
be defi nitely identifi ed and it remains to be determined whether it is
really involved in age-related defi cits in synaptic plasticity.
In addition to glutamate, NMDA-R activation requires the
binding of a co-agonist at the strychnine-insensitive glycine site
(Johnson and Ascher, 1990). Recent developments indicate that the
amino acid d-serine, rather than glycine itself, is the main endog-
enous co-agonist of NMDA-R in cerebral areas involved in memory
processes, and in the hippocampus in particular (Mothet et al.,
2000). Moreover, it has been shown that the induction of LTP both
in hippocampal cultures and in slice preparations is blocked when
d-serine is absent from the extracellular space (Yang et al., 2003;
Mothet et al., 2006). These results suggest a possible contribution of
d-serine to the impairment of NMDA-R activation and functional
plasticity that takes place in the aging brain, and consequently a
role for the amino acid in age-related memory defects.
In this report, we present our recent experimental results indi-
cating that the manipulation of d-serine levels at the synapse may
be an alternative strategy for the development of new treatments
for cognitive aging.
MATERIALS AND METHODS
All animal experiments were performed in strict compliance with
the European Communities Council Directive (86/809/EEC) regard-
ing the care and use of animals for experimental procedures and
In the general decline that gradually develops with age, learning and
memory defi cits are frequent features. Studies in animal models of
aging have confi rmed the occurrence of cognitive decline with age and
shown that it concerns several forms of memory, including spatial,
associative and long-term memory (Winocur and Moscovitch, 1990;
Gallagher and Rapp, 1997; Miyamoto, 1997; Houston et al., 1999; Norris
and Foster, 1999; Clayton et al., 2002a; Sykova et al., 2002; Rosenzweig
and Barnes, 2003; Gruart et al., 2008). These studies emphasize the
role of the hippocampus and related structures in age-related memory
defi cits, demonstrating that the functional properties of hippocam-
pal networks are particularly vulnerable to aging (Landfi eld, 1988;
Foster and Norris, 1997; Thibault et al., 2007). In particular, the study
of long-lasting modifi cations of glutamatergic neurotransmission
such as long-term potentiation (LTP), long-term depression and
LTP reversal (depotentiation), now considered to be the functional
substrates of memory encoding (Izquierdo and Medina, 1995; Kim
and Linden, 2007), have demonstrated changes in the threshold and/
or magnitude of synaptic plasticity with age (Foster, 1999; Barnes,
2003). Although several mechanisms may account for these changes
(Rosenzweig and Barnes, 2003; Foster, 2007), most of these studies
have focused on the activation of the N-methyl-d- aspartate subtype
of glutamate receptors (N-methyl-d-aspartate receptors, NMDA-
R). Indeed, these receptors play a major role in regulating synaptic
strength, by means of their high permeability to Ca2+, which triggers
the activation of specifi c protein kinases and phosphatases (Wang et
al., 1997). Although evidence indicates that NMDA-R activation is
Contribution of the D-Serine-dependent pathway to the
cellular mechanisms underlying cognitive aging
B. Potier1, F. R. Turpin1†, P .-M. Sinet1, E. Rouaud1, J.-P . Mothet2†, C. Videau1, J. Epelbaum1,
P . Dutar1 and J.-M. Billard1*
1 Centre de Psychiatrie et Neurosciences, INSERM, U894, Faculté de Médecine, Université Paris Descartes, Paris, France
2 Laboratoire de Neurobiologie Cellulaire et Moleculaire, CNRS UPR 9040, Gif sur Yvette, France
An association between age-related memory impairments and changes in functional plasticity
in the aging brain has been under intense study within the last decade. In this article, we show
that an impaired activation of the strychnine-insensitive glycine site of N-methyl-D-aspartate
receptors (NMDA-R) by its agonist D-serine contributes to defi cits of synaptic plasticity in
the hippocampus of memory-impaired aged rats. Supplementation with exogenous D-serine
prevents the age-related defi cits of isolated NMDA-R-dependent synaptic potentials as well as
those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous
levels of D-serine are reduced in the hippocampus with aging, that correlates with a weaker
expression of serine racemase synthesizing the amino acid. On the contrary, the affi nity of
D-serine binding to NMDA-R is not affected by aging. These results point to a critical role for
the D-serine-dependent pathway in the functional alterations of the brain underlying memory
impairment and provide key information in the search for new therapeutic strategies for the
treatment of memory defi cits in the elderly.
Keywords: memory, serine racemase, NMDA receptors, hippocampus, synaptic plasticity
Thomas C. Foster, University of
Jose M. Delgado-Garcia, University
Pablo de Olavide, Spain
Michael R. Foy, Loyola Marymount
Michelle Nicolle, Wake Forest
University School of Medicine, USA
J.-M. Billard, Centre de Psychiatrie et
Neurosciences, INSERM, U894,
Faculté de Médecine, Université Paris
Descartes, 2 ter rue d’ Alésia, 75014
Paris, France. e-mail: jean-marie.
F . R. Turpin and J.-P . Mothet, INSERM
U862, Neurocentre Magendie, 146 rue
Léo Saignat, Bordeaux 33077 , France.
Frontiers in Aging Neuroscience www.frontiersin.org February 2010 | Volume 2 | Article 1 | 2
Potier et al.
D-Serine in cognitive aging
approved by the local ethics committee. Experiments were conducted
on “adult” (3–6 months old, n = 58) and “aged” (25–33 months old,
n = 57) male Sprague-Dawley rats purchased from IFFA-CREDO
(France). Rats were maintained on a 12 h controlled light–dark cycle
at a constant temperature (22 ± 2°C) with ad libitum access to food
The task was a modifi ed version of the Morris water maze (Morris
et al., 1982). Each rat was fi rst trained to swim to a visible platform
(13 cm × 13 cm) placed in a fi xed position in one of the quadrants
of a circular pool (150 cm in diameter), painted black and fi lled with
water at 21–22°C. The platform was 2 cm above the surface of the
water, and could easily be seen by the rats. The time (escape latency)
and distance swum before fi nding the platform were then deter-
mined. If the rat did not fi nd the platform within 60 s, it was placed
on the platform and left for 35 s. Four trials per day were carried out
for 6 days. A different (randomly determined) starting location was
used for each trial. Visual cues were present around the pool.
During the second phase of testing (place version), the rat was
trained to swim to an invisible platform that was located at a posi-
tion different from that used during the visible platform trial. The
platform was located 2 cm below the surface of the water. Four trials
per day were carried out for 6 days. The position of the platform
remained the same for the 6 days of the test. For each trial, the time
and distance to platform and swim speed were measured using
SmartC software. On day 7 (probe trial), the hidden platform was
removed and the time spent by the rat swimming through the dif-
ferent quadrants, including the quadrant in which the platform was
situated during place learning, was registered over a 90-s period.
Transverse hippocampal slices (400 µm) were obtained from rats
anesthetized with halothane before decapitation. Slices were pre-
pared in ice-cold artifi cial cerebrospinal fl uid (aCSF) and placed in
a holding chamber for at least 1 h. The composition of aCSF was
(in mM): NaCl 124, KCl 3.5, MgSO4 1.5, CaCl2 2.3, NaHCO3 26.2,
NaH2PO4 1.2, and glucose 11. A single slice at a time was transferred
to the recording chamber and continuously superfused with aCSF
pre-gassed with 95% O2/5% CO2.
Extracellular fi eld excitatory postsynaptic potentials (fEPSPs)
were obtained at room temperature from the apical dendritic layer
of the CA1 area after electrical stimulation (100 µs duration) of
Schaffer collaterals and commissural fi bers. Input/Output (I/O)
curves of NMDA-R-mediated synaptic responses were plotted for
adult and aged rats from slices superfused for 40 min in low Mg2+
aCSF supplemented with the α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA)/kainate receptor antagonist 2,3-
(NBQX, 10 µM). A knife cut was introduced to separate CA3 and
CA1 in order to prevent the propagation of epileptiform discharges.
The slope of three averaged fEPSPs was measured and plotted
against different intensities of stimulation (from 0 to 500 µA) using
Acquis 1 software (CNRS, Paris, France).
For experiments investigating LTP, two different conditioning
stimuli were delivered after a baseline acquisition of 15 min. In the
case of high frequency stimulation (HFS), the stimulus consisted of
two trains (100 Hz for 1 s) separated by a 20-s interval. In the case
of theta-burst stimulation (TBS), it consisted of fi ve trains of four
pulses at 100 Hz separated by 200 ms. This sequence was repeated
three times with an interval of 10 s. In both HFS and TBS experi-
ments, testing with a single pulse was then resumed for 60 min to
determine the level of stable LTP.
In order to investigate the depotentiation of synaptic transmis-
sion, a low frequency conditioning stimulus (LFS, 900 pulses, 1 Hz)
was applied 1 h after HFS delivery. Tests with a single pulse were
resumed for at least 40 min after LFS. To study the effects of exog-
enous d-serine, the co-agonist was applied throughout the record-
ing except for the depotentiation paradigm where it was applied
50 min after HFS delivery, once LTP was stabilized. The co-agonist
was then maintained until the end of the recording.
[3H] L-689.560 (22.41 Ci/mmol or 0.83 TBq/mmol) was obtained
from Tocris Cookson, Bristol (UK). The brain of adult and aged
rats were quickly removed, frozen for 30 s in isopentane at −40°C
and stored at −80°C. Coronal sections (14 µm) were cut on a cryo-
stat at −15°C and mounted onto glass slides. Brain sections were
preincubated with 50 mM Tris acetate buffer (pH 7.0) at room
temperature for 30 min to remove endogenous free d-serine. For
competition studies, sections were incubated with Tris acetate buffer
supplemented with 10 µM strychnine and 1 nM [3H] L-689.560
containing d-serine, glycine and L-689.560 at 4°C for 120 min.
After incubation, the slides were rinsed four times with cold Tris
acetate buffer (4°C) for a total of 20 s and then in distilled water
at the same temperature for 5 s. After drying, slides were placed on
[3H]- sensitive fi lm (Hyperfi lm-3H, Amersham) for two months at
4°C. The fi lm was developed with Dektol (Kodak) for 2 min and
analyzed using an X-ray fi lm digitizer, RAG500, and Biocom soft-
ware (Les Ulis, France).
DETERMINATION OF D-SERINE CONTENT IN HIPPOCAMPAL SLICES
Free amino acids were extracted from pooled brain slices with
trichloroacetic acid and stored at −80°C until assay. Two different
procedures were used to determine d-serine content. The fi rst tech-
nique quantifi ed d-serine using a chemiluminescent assay based on
the dAAO/HRP/luminol system (Wolosker et al., 1999). In the sec-
ond approach, high-performance liquid chromatography (HPLC)
analysis was performed using pre-column derivatization of samples
with O-phthaldialdehyde and N-acetyl cysteine. Dia-stereo-isomers
were resolved in the isocratic phase on a C18 Nova Pak column. In
both procedures, the amount of d-serine was adjusted to protein
content as determined by a Bio-Rad DC protein assay (Bio-Rad
Laboratories, Hercules, CA, USA). Standards of d-serine were used
to normalize the results.
SEMI-QUANTITATIVE IMMUNOBLOT ANALYSIS
Western blot analysis was performed as described previously (Puyal
et al., 2002). Briefl y, after lysis, protein extracts were subjected to
electrophoresis (12% SDS-polyacrylamide gel) and electroblotted
onto PVDF membranes (Immobilon-P, Millipore). Membranes
were probed with a polyclonal antibody to dAAO (1:2000, Nordic
Immunological Laboratories, Tilburg, The Netherlands), a polyclo-
nal antibody to serine racemase (1:200, Santa Cruz Biotechnology,
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Potier et al.
D-Serine in cognitive aging
Wiltshire, UK) or a monoclonal α-Tubulin antibody (1:400, Santa
Cruz Biotechnology) for 1 h at room temperature. After wash-
ing, they were incubated with peroxidase-conjugated anti-rabbit,
anti-goat and anti-mouse immunoglobulin G respectively (IgG;
1:2000, Vector Laboratories Burlingame, USA). Immunoblots were
developed using enhanced chemiluminescence (ECL; Amersham
Biosciences, Little Chalfont Buckinghamshire, UK). Molecular sizes
were estimated by separating prestained molecular weight markers
(6.5–175 kDa) in parallel (New England BioLabs, Hertfordshire,
UK). Protein bands of interest were analyzed by measuring opti-
cal density using scanning densitometry. Densitometric results for
serine racemase and dAAO were normalized to the density of α-
Tubulin. Each blot included three successive dilutions of samples
for the quantifi cation of variations in density.
QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (RT-PCR)
Total RNA was prepared from frozen tissues using the RNeasy Midi
kit (Qiagen). Total RNA was converted to cDNA using M-MLV
reverse transcriptase and random hexanucleotide primers designed
using PrimerExpress (Applied Biosystems), as follows. Serine race-
mase: (sense: 5′-GATTCGAGGTGCCCTTAACG-3′; antisense:
5′-TTGGGCTTCCCTT CTAAAGTATCA-3′), d-amino acid oxi-
dase (sense: 5′-CCTCAGGTCCG GCTAGAAAGA-3′; antisense:
5′-GGATGACCTCTGCACTTGAAGAT-3′), glial fi brillary acidic
protein (GFAP) (sense: 5′-TGACCGCTTTGCTAGCTACATC-
3′; antisense: 5′-GCGCCTTGTT TTGCTGTTC-3′) and MAP2
(sense: 5′-AGATCAGAAAGACTGGTTCATCGA-3′; antisense: 5′-
CAGCTAAACCCCATTCATCCTT-3′). PCR reactions (20 µl total
volume) were performed with Sybr Green PCR master mix using
standard protocols on an ABI 7000 Sequence Detection System.
Raw Ct values were obtained with SDS 2.0 and were used for rela-
tive expression calculations.
All drugs were applied in aCSF and included NBQX (10 µM in
DMSO), d-2-amino-5-phosphonovalerate (d-APV, 30–80 µM),
d-serine (2–200 µM), l-serine (100 µM), L689.560 (10 µM)
and nifedipine (50 µM). Drugs were purchased from Tocris
All results are expressed as means ± SEM. Behavioral results and
time-course of synaptic plasticity were analyzed by one or two-ways
analyses of variance (ANOVA) with repeated measures, followed
by post hoc multiple comparisons tests (Fisher’s PLSD) (Statview®).
The sensitivity of NMDA-R-mediated fEPSPs to exogenous d- serine
was determined using Student’s paired t-test while the effects of
age on other parameters (magnitude of LTP over the last 15 min of
recordings, expression of proteins involved in the d-serine pathway,
d-serine levels) were analyzed using an unpaired t-test. In all cases,
differences were considered signifi cant when p ≤ 0.05.
Spatial learning was explored in adults (n = 10) and aged animals
(n = 12) using different versions of the Morris water maze protocol.
As illustrated in Figure 1A (left), the distance swum to fi nd the plat-
form differed greatly between groups (p < 0.0001) and a signifi cant
interaction between group and time was observed, since aged rats
swam longer distances before reaching the hidden platform in the
“place” version of the task (interaction of distance × group/age,
p < 0.01). When each group was examined separately, adult rats effi -
ciently learned the position of the platform across trials, as demon-
strated by a signifi cant decrease in the distance swum before fi nding
the platform in each subsequent trial (p < 0.005), whereas aged rats did
not (p = 0.3). When animals were tested 24 h after the end of the learn-
ing sessions, adult rats spent more time swimming in the quadrant in
which the platform was located during place learning, whereas aged
ones did not (Figure 1A, right). In contrast, the two groups of animals
did not differ in swim speed during place learning (15.3 ± 0.9 cm/s in
adults vs. 12.4 ± 1.1 cm/s in aged animals) and in distance swum or
time to escape onto a visible platform in the cued version of the maze
(not shown). These results indicate that aged rats are signifi cantly
impaired with respect to spatial learning and that these defi cits are
independent of sensory and/or motor dysfunctions.
AGE-RELATED CHANGES IN SYNAPTIC PLASTICITY
Since spatial learning has been associated with the capacity of hip-
pocampal neuronal networks to adapt synaptic strength to ongo-
ing changes in presynaptic activity (Izquierdo and Medina, 1995;
Lynch, 2004; Kim and Linden, 2007), we compared the induction
and expression of synaptic plasticity in hippocampal slices from
adults and aged rats, including high-frequency (HFS) and theta-
burst (TBS)-patterns to study LTP, and HFS followed 1 h later by
low frequency stimulation (LFS) to evaluate depotentiation (see
Materials and Methods).
Following the HFS protocol, recordings in slices from adult rats
(n = 20) showed a long-term increase in synaptic transmission
(Figure 1B, left) of 48.7 ± 5.4%, averaged from the last 15 min of
recordings (Figure 1B, right). LTP generated in slices from aged rats
(n = 13) had a magnitude (50.4 ± 8.7%) similar to that recorded
in adults (Figure 1B, right). However, it is worth noting that the
fEPSPs amplitude rapidly returned to baseline levels in slices from
adult rats (n = 10) when HFS was delivered in the presence of the
NMDA-R antagonist d-APV (80 µM), whereas a long lasting poten-
tiation still remained under the same conditions in slices from aged
animals (17.1 ± 4.9%, n = 10 when averaged from the last 15 min
of recordings). HFS-induced LTP was prevented in aged rats only
when the conditioning stimulus was delivered in the presence of
d-APV and of the voltage-gated calcium channel (VGCC) blocker
nifedipine (50 µM) (Figure S1 in Supplementary Material).
Under control conditions, a low frequency stimulus (1 Hz,
15 min) delivered 1 h after HFS induced an LTP reversal or depo-
tentiation in slices from adult animals (n = 9) but had little effect
on slices from aged rats (n = 19) (Figure 1C, left). Indeed, the per-
cent reversal calculated from the last 15 min of recordings averaged
32.3 ± 2.7% in the former and only 10.7 ± 2.3% in the latter, indi-
cating that LTP reversal was affected by age (Figure 1C, right).
In the theta-burst paradigm of stimulation (TBS), synaptic trans-
mission was potentiated in slices from adult rats (n = 12) (Figure 1D,
left), resulting in a 35.4 ± 2.4% increase in amplitude. TBS-induced
LTP was also recorded in slices from old animals (n = 13) (Figure 1D,
left) but the percent increase (19.4 ± 4.7%) was signifi cantly lower
than that reached in adult rats (p = 0.02) (Figure 1D, right). Contrary
to our results with HFS-induced LTP, the long-lasting increase in
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Potier et al.
D-Serine in cognitive aging
synaptic transmission induced by TBS was totally blocked both in
adult (n = 6) and aged rats (n = 7) when the conditioning stimulus
was delivered in the presence of d-APV (80 µM).
AGE-RELATED CHANGES IN ISOLATED NMDA-R-MEDIATED SYNAPTIC
RESPONSES: EFFECTS OF D-SERINE
Except for the HFS-induced LTP in aged rats in which VGCC were
also concerned, the specifi c antagonist d-APV alone was able to
prevent the expression of synaptic plasticity in both groups of
animals, confi rming the pivotal role of NMDA-R in this process.
We therefore subsequently looked for changes in the behavior of
isolated NMDA-R-mediated synaptic potentials that could account
for these age-related changes in synaptic plasticity.
Synaptic potentials were recorded in low-Mg2+ medium sup-
plemented with the AMPA receptor antagonist NBQX (10 µM),
and were blocked by d-APV (30 µM) added at the end of the
recordings (Figure 2A). I/O curves plotted for data collected
using 53 slices from 24 adult rats and 37 slices from 19 aged
FIGURE 1 | Spatial learning and hippocampal synaptic plasticity are
impaired in aged rats. (A, left) Comparison of the distance swum before
escaping onto the hidden platform over 6 days of training in adult and aged
rats (##p < 0.01, repeated measures ANOVA). (A, right) Comparison of time
spent by rats swimming through the different quadrants, including quadrant
4, where the platform was situated during place learning, registered over a
90-s probe trial (#p < 0.05, unpaired t-test). (B, left) Time-course of LTP
induction in adult and aged rats by HFS (arrow). (B, right) Comparison of mean
LTP magnitude (±SEM) calculated for the last 15 min of recording. (C, left)
Time course of depotentiation of previously HFS-potentiated synaptic
responses induced in adult and aged rats by LFS. (C, right) Comparison of
depotentiation magnitude (±SEM) calculated for the last 15 min of recording.
(D) Illustration of results obtained with TBS protocols. (#p < 0.05, ##p < 0.01,
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Potier et al.
D-Serine in cognitive aging
animals at multiple stimulus intensities (Figure 2B) indicated
that the amplitude of these NMDA-R synaptic potentials was sig-
nifi cantly reduced in aged rats (interaction of strain × intensity,
p = 0.01).
Because NMDA-R synaptic potentials were also antagonized
by L689.560 (10 µM), the specifi c blocker of the glycine modula-
tory site, we wondered whether changes affecting this binding site
could underlie the age-related decrease in NMDA-R activation.
We therefore checked the responsiveness of isolated NMDA-R-
mediated synaptic potentials to an exogenous application of the
specifi c agonist d-serine. As illustrated in Figure 2C, the amino
acid dose-dependently enhanced these synaptic responses, but its
potency was signifi cantly higher in slices from aged rats than in
those from young adults, regardless of the concentration of the
co-agonist. Consequently, defi cits in NMDA-R synaptic poten-
tials were prevented in slices from aged animals supplied with
d-serine (see Figure 2D). In contrast, l-serine (100 µM), the pre-
cursor of d-serine, did not signifi cantly alter isolated NMDA-R
synaptic potentials either in slices from adults (n = 10) or from
old rats (n = 9).
EFFECTS OF D-SERINE ON AGE-RELATED DEFICITS IN
Since isolated NMDA-R potentials were rescued from age-related
alterations by boosting the activation of the glycine modulatory site,
we asked whether defi cits in the expression of synaptic plasticity in
aged rats could also be reversed by the same procedure.
In slices from adults (n = 12), d-serine did not affect the magnitude
of HFS-induced LTP, whereas it signifi cantly increased the amplitude
of potentiation in slices (n = 10) from old animals (p < 0.05, Figure 3A,
left). Under these conditions, in which the agonist saturated the glycine
binding sites of the NMDA-R, HFS-induced LTP was higher in aged
rats (77.8 ± 13.9%) than in younger ones (55 ± 11.6%) (Figure 3A,
right), although this difference was not statistically relevant.
The effects of exogenous d-serine on depotentiation were then
investigated. When the NMDA-R co-agonist was present in the aCSF
during LFS delivery, the magnitude of depotentiation in slices from
aged rats (n = 9) was signifi cantly enhanced (p < 0.05), whereas no
effect was seen in slices from adult rats (n = 6) (Figure 3B, left).
Under these conditions, the age-related alteration of depotentiation
was therefore prevented by d-serine (Figure 3B, right).
FIGURE 2 | D-Serine prevents age-related defi cits in isolated NMDA-R
synaptic potentials. (A) Representative NMDA-R-mediated synaptic potential
induced by the stimulation of glutamatergic afferents (fi rst arrow) and recorded in
an adult (pink trace) and in an aged (blue trace) rat for a stimulus intensity of
400 µA, and the loss of the synaptic response in the presence of D-APV (30 µM)
(black trace). (B) Plot of the mean NMDA-R-mediated fEPSP slope (±SEM) against
increasing stimulus intensities, recorded in control aCSF in adult and aged rats. (C)
Bar graph of the mean increase in NMDA-R-mediated fEPSP slope (±SEM) as a
function of D-serine concentration in adult and aged rats (#p < 0.05 and ##p < 0.01,
unpaired t-test). Sample sizes are indicated in parentheses above the bars. (D) Plot
of the mean NMDA-R-mediated fEPSP slope against increasing stimulus
intensities, recorded in D-serine-supplemented aCSF in adult and aged rats.
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Potier et al.
D-Serine in cognitive aging
Regarding the effects of by d-serine on TBS-induced LTP, the
magnitude averaged over the last 15 min of recording was signifi -
cantly increased in slices from both young adult (n = 11) and aged
(n = 11) animals, but the increase was greater in the latter group
(Figure 3A, left). Consequently, the age-related defi cit in TBS-
induced LTP was alleviated by the exogenous application of the
NMDA-R co-agonist (Figure 3C, right).
D-SERINE-DEPENDENT METABOLIC PATHWAYS IN AGING
The impaired activation of the NMDA-R glycine modulatory site
by endogenous d-serine during aging may be due to changes in
receptor affi nity and/or the availability of the co-agonist in aged
d-serine binding sites were abundantly present in the stratum
radiatum and stratum oriens of the CA1 hippocampal region as
well as in the dentate gyrus of both adult (n = 3) and aged (n = 3)
animals, as revealed by the potent radioligand [3H] L689.560. This
ligand was dose-dependently displaced by unlabeled d-serine (from
3 nM to 300 µM) to a similar extent in the two groups of animals
and in all hippocampal subregions (Figures 4A–C), indicating that
the affi nity of the NMDA-R glycine binding site for d-serine was
not altered by age.
To determine whether aging alters the availability of the endog-
enous ligand, two different methods were applied. In the fi rst, the
levels of endogenous d-serine were determined by a specifi c chemi-
luminescent assay based on the d-amino acid oxidase/horserad-
ish peroxidase/luminal system (Wolosker et al., 1999). With this
method, we found that levels of the amino acid were signifi cantly
decreased in hippocampal tissues of old rats (n = 7) when com-
pared with adults (n = 9) (Figure 4D, left). In parallel, the amounts
of d-serine as well as those of its precursor l-serine were determined
in a different pool of animals using conventional HPLC (Figure 4D,
right). This experiment confi rmed that hippocampal tissues derived
from old rats (n = 7) had reduced levels of d-serine whereas the
FIGURE 3 | D-serine alleviates the age-related defi cit in synaptic plasticity.
(A, left) Effects of D-serine (100 µM) on the magnitude of HFS-induced LTP
calculated for the last 15 min of recording. (A, right) Time-course of LTP induced
in adult and aged rats in the presence of the NMDA-R co-agonist. (B, C) Results
obtained with TBS and depotentiation protocols respectively (#p < 0.05,
##p < 0.01, unpaired t-test).
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Potier et al.
D-Serine in cognitive aging
amount of l-serine tended to be higher (Figure 4D, right). As a
consequence, the d/L-serine ratio was signifi cantly lowered from
0.42 in young adult rats to 0.06 in old animals (p < 0.001).
This age-related decrease in d/L-serine ratio suggests that d-
serine metabolism is impaired. We therefore checked for the expres-
sion of serine racemase (SR) and d-amino-acid oxidase (dAAO),
the enzymes synthesizing and degrading d-serine respectively.
In Western blots (Figure 5A), we detected a single band of 37-
kDa corresponding to the predicted molecular mass of SR. Semi-
quantitative analysis of samples from fi ve young adult and fi ve
aged rats showed a signifi cant age-related decrease in enzyme
expression (−42%, p < 0.01) once the amount of protein loaded
was normalized to α-tubulin (Figure 5B). In contrast, the expres-
sion of dAAO, identifi ed as a 39-kDa band, (Figure 5A) was not
affected in aged animals (Figure 5B).
Similar results were obtained for mRNA levels. Indeed, quan-
titative PCR showed that mRNA levels for SR were signifi cantly
decreased in the hippocampus of aged rats (p < 0.01), whereas those
for dAAO were not modifi ed (Figure 5C). It is worth noting that
the expression of the glutamate metabolizing enzyme glutamine
synthetase is not affected, indicating that the glutamine/glutamate
cycle is not altered by aging.
FIGURE 4 | Aging does not alter the affi nity of D-serine binding sites but
decreases D-serine availability. Representative mean displacement curves of
specifi c [3H] L689.560 binding by D-serine in the stratum radiatum of the CA1
(A), the stratum oriens of the CA1 (B) and the dentate gyrus (C) respectively of
adult and aged rats. (D, left). Bar graph of mean D-serine levels (±SEM)
determined by the chemiluminescent assay in adult and aged rats. (D, right) Bar
graph of mean D-serine and L-serine levels (±SEM) determined by HPLC in adult
and aged rats (##p < 0.01, unpaired t-test).
Frontiers in Aging Neuroscience www.frontiersin.org February 2010 | Volume 2 | Article 1 | 8
Potier et al.
D-Serine in cognitive aging
In the last century, the mortality of the world population has been
substantially delayed by improvements in hygiene and nutrition
and by better treatment for illnesses. However, this increase in life
expectancy is unfortunately associated with defi cits in learning
and memory (cognitive) or in motivation (emotional) (Grady and
Craik, 2000; Craik and Bialystok, 2006; Luo and Craik, 2008). Over
the past few decades, extensive behavioral experiments in animal
models of aging, mainly conducted in aged rodents of different
strains and species, have clearly shown how effi cient learning and
memory in young individuals is slowed down with age, while for-
getfulness is accelerated (Winocur and Moscovitch, 1990; Gallagher
and Rapp, 1997; Miyamoto, 1997; Houston et al., 1999; Norris and
Foster, 1999; Clayton et al., 2002b; Sykova et al., 2002; Gruart et al.,
2008). In accordance with these studies, we have shown in our inves-
tigation that spatial learning is altered in aged Sprague-Dawley rats,
independent of sensory and/or motor dysfunctions. Identifying
the functional changes in the brain that underlie cognitive aging
is now of particular importance in order to improve quality of life
in the elderly.
In the present report, we show that age-related defi cits in spatial
memory are correlated with changes in the ability of the aging
brain to drive synaptic plasticity in neuronal networks of the hip-
pocampus (see Junjaud et al., 2006; Mothet et al., 2006; Billard and
Rouaud, 2007). When moderate synaptic activation is concerned,
such as the activation evoked by TBS paradigms, the expression of
LTP is impaired in aged animals (Moore et al., 1993; Tombaugh et
al., 2002). We show that this form of LTP is blocked by the specifi c
NMDA-R antagonist d-APV in both young adult and aged animals.
Its impairment in the aging hippocampus is therefore likely to
refl ect a weaker activation of these subtypes of glutamatergic recep-
tors. In contrast, age-related defi cits in LTP are overridden by the
FIGURE 5 | Serine racemase expression is reduced in aged rats. (A, left)
Immunoblots for α-tubulin (upper band), DAAO (middle band) and serine
racemase (lower band) in adult and aged rats. 10 µg of protein were loaded per
lane. (B, right) Immunoblots obtained with different amounts of protein loaded
(2.5–15 µg/lane) in order to evaluate relative optical density variations. (B, left)
Quantitative analysis of immunoreactivity for serine racemase and DAAO in adult
and aged rats, normalized to α-tubulin. (B, right) Graph illustrating the linear
relationship between optical density and the amount of protein loaded. (C) Bar
graphs of mRNA levels of serine racemase and DAAO normalized to GFAP
transcripts in adult and aged rats (##p < 0.01, unpaired t-test). AU, arbitrary unit.
Frontiers in Aging Neuroscience www.frontiersin.org February 2010 | Volume 2 | Article 1 | 9
Potier et al.
D-Serine in cognitive aging
N-Methyl-d-aspartate receptors activation relies on a voltage-
dependent blockade by magnesium (Nowak et al., 1984) that is not
affected in aged animals (Potier et al., 2000). It also needs the bind-
ing of a co-agonist at the strychnine-insensitive glycine modulatory
site (Johnson and Ascher, 1987). In the last few years, the amino
acid d-serine has been proposed as the main endogenous co-agonist
of NMDA-R in the hippocampus, since its function, as revealed
by biochemical and electrophysiological methods, are weakened
by the selective degradation of d-serine by the degrading enzyme
dAAO (Mothet et al., 2000; Yang et al., 2003). Our study shows
that exogenous d-serine enhances isolated NMDA-R- mediated
synaptic responses in both young adult (see also Watanabe et al.,
1992; Martina et al., 2003; Krasteniakov et al., 2005) and aged rats
but that the potency of the co-agonist is higher in the latter group.
In addition, we have found that d-serine is able to reverse the age-
related defi cits in NMDA-R-mediated synaptic potentials and syn-
aptic plasticity, including TBS-induced LTP and depotentiation, as
has been previously reported in senescence-accelerated (SAMP8)
mice (Yang et al., 2005). These results therefore indicate that the
reduced activation of NMDA-R glycine binding sites by endog-
enous d-serine is a potent mechanism underlying the age-related
defi cits in synaptic plasticity.
The increased effi cacy of d-serine supplementation with age
may refl ect changes in the degree of receptor saturation, deter-
mined by the specifi c affi nity of the glycine modulatory site and/or
changes in endogenous d-serine levels. Our binding studies have
indicated that receptor affi nity for d-serine remains unaffected in
aged Sprague-Dawley rats, as reported in other strains of rats and
in mice (Miyoshi et al., 1990; Nagata et al., 1998). In contrast, we
provide evidence to show that endogenous levels of d-serine are
dramatically reduced with aging. This result differs from previous
studies showing no changes in d-serine levels in aged Wistar rats
(Hashimoto et al., 1993) and SAMP8 mice (Nagata et al., 1998). A
possible explanation for this discrepancy lies in differences between
species or strains. Nevertheless, we have recently found that d-serine
levels are also decreased in the hippocampus of aged Wistar rats
(Turpin et al., 2009). An alternative possibility is that age-related
changes in d-serine levels occur in restricted areas of the brain,
since we used isolated hippocampi in our experiments whereas
the study of Hashimoto et al. (1993) was performed with whole
The fact that d-serine levels are decreased while those of its
precursor l-serine are simultaneously increased strongly argues
for changes in the d-serine biosynthetic pathway during aging.
Accordingly, we found that the expression of the synthesizing
enzyme serine racemase is weakened in old rats, both at the mRNA
and protein levels, whereas dAAO is not affected. It remains to
be determined whether the activity of serine racemase is also
altered. Other mechanisms amplifying the age-related decrease
in the synaptic availability of d-serine, such as changes in its dif-
fusion rate in the extracellular space (Sykova et al., 1998, 2002)
and/or an increased reuptake by membrane transporters in both
neuronal and glial cells (see Billard, 2008 for a review), remain to
The ability of d-serine to prevent age-related defi cits in synaptic
plasticity makes this amino acid an attractive tool for the reduc-
tion of memory dysfunction in the aged. It is worth noting that
stronger synaptic activation induced by HFS protocols, indicating
that additional mechanisms have come into play to compensate
for the impaired NMDA-R activation. Indeed, synaptic plasticity is
completely blocked in the hippocampus of aged rats only if HFS is
delivered in the presence of d-APV and of the antagonist nifedipine,
indicating that VGCCs also contribute to HFS-induced LTP in aged
animals, as previously suggested (Shankar et al., 1998). Whatever
the mechanisms that compensate for impaired NMDA-R activation,
behavioral experiments reveal that they are not helpful in maintain-
ing memory capacity in aged subjects at young adult levels. It is
worth noting that VGCC activation is not related to memory acqui-
sition, but only to the retention of information (Borroni et al., 2000)
and that the excessive activation of the L-subtype of VGCCs may be
detrimental to memory formation (Liu et al., 2003). Furthermore,
we have shown that LTP is rapidly depotentiated in adult but not
in aged animals, using an LFS protocol (Kamal et al., 1998). Since
LTP saturation disrupts memory formation in young rats (Moser
and Moser, 1999), a reduced capacity of hippocampal networks
to be reset from potentiated levels may also constitute a synaptic
mechanism contributing to cognitive aging. On the other hand, it
has been reported that HFS-induced LTP is impaired in aged mice
in vivo (Gruart et al., 2008), indicating that compensatory mecha-
nisms involving VGCCs do not occur in this species. Alternatively,
this discrepancy with our own results could be due to differences
in experimental protocols (in vivo vs. in vitro, age of the animals,
number of conditioning trains of stimuli).
As discussed above, age-related changes in synaptic plasticity
are likely to refl ect a shift in calcium sources, with a weaker role
for NMDA-R and an increased contribution of VGCCs and intra-
cellular stores with different kinetic properties, at least in the rat
hippocampus (Kumar and Foster, 2005; Gant et al., 2006; Foster,
2007; Thibault et al., 2007). Our investigations confi rm the age-
related impairment in NMDA-R activation, as demonstrated by
the decrease in the magnitude of isolated NMDA-R-dependent
synaptic potentials in old animals (see also Barnes et al., 1997; Potier
et al., 2000). Considering that only postsynaptic determinants are
concerned (Burke and Barnes, 2006), it could be expected that a
decrease in receptor number underlies this impairment. Accordingly,
Clayton et al. (2002b) have reported that age- associated changes
in LTP expression can be mimicked by reducing the density of
NR2B subunits. Several studies have also shown that the number
of NMDA receptors is decreased in the hippocampus of aged rats
and mice, and that this decrease is correlated with memory impair-
ments. However, this has not been seen in other studies and many
investigations instead support the idea that NMDA-R density is
unchanged or even increased during aging (see Billard et al., 1997
for a review). In addition, it has recently been shown in aged Lou/
C/Jall rats that NMDA-R number is signifi cantly reduced without
changes in memory abilities or synaptic plasticity (Kollen et al.,
2010). Finally, the present study shows that the magnitude of iso-
lated NMDA-R-mediated potentials is not different in young adult
and aged rats when all NMDA-Rs are recruited with saturating con-
centrations of the co-agonist d-serine. Taken together, these data
indicate that an age-related decrease in NMDA-R number is not
an essential mechanism in the weaker response of these receptors
in aged animals, but rather the changes in their functional and/or
pharmacological properties that are concerned.
Frontiers in Aging Neuroscience www.frontiersin.org February 2010 | Volume 2 | Article 1 | 10
Potier et al.
D-Serine in cognitive aging
defects in spatial memory in aged rats (Aura and Riekkinen, 2000)
and the disruption of the hippocampus-dependent associative eye-
blink conditioning in old rabbits (Thompson and Disterhoft, 1997)
are reduced by the partial agonist d-cycloserine, which also allevi-
ates the age-related defi cit in NMDA-R-mediated synaptic plasticity
by acting on the glycine-binding site (Billard and Rouaud, 2007).
Unfortunately, the possibility of the long-term treatment of cognitive
defects with large doses of d-cycloserine or with d-serine itself has
been discarded, because the former leads to side-effects in the central
nervous system while the latter induces the DAAO-dependent necro-
sis of the terminal portions of the proximal renal tubules (Williams
and Lock, 2004; Krug et al., 2007). Alternatively, the fact that serine
racemase is selectively affected in aged tissues opens new perspectives
in the search for relevant strategies to reduce the memory impairment
associated with aging, as has been recently suggested for neurological
disorders including schizophrenia and Alzheimer’s disease (Labrie et
al., 2009; Tsai and Lin, 2009, see Billard, 2008 for a review).
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential confl ict
Received: 10 November 2009; paper pend-
ing published: 17 November 2009; accepted:
07 January 2010; published online: 05
Citation: Potier B, Turpin FR, Sinet P-M,
Rouaud E, Mothet J-P, Videau C, Epelbaum
J, Dutar P and Billard J-M (2010)
Contribution of the d-Serine-dependent
pathway to the cellular mechanisms under-
lying cognitive aging. Front. Ag. Neurosci.
2:1. doi: 10.3389/neuro.24.001.2010
Copyright © 2010 Potier, Turpin, Sinet,
Rouaud, Mothet, Videau, Epelbaum, Dutar
and Billard. This is an open-access article
subject to an exclusive license agreement
between the authors and the Frontiers
Research Foundation, which permits unre-
stricted use, distribution, and reproduc-
tion in any medium, provided the original
authors and source are credited.
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