Enhanced Long-Term Synaptic Depression
in an Animal Model of Depression
Roman Holderbach, Kristin Clark, Jean-Luc Moreau, Josef Bischofberger, and Claus Normann
Background: A growing body of evidence suggests a disturbance of brain plasticity in major depression. In contrast to hippocampal
neurogenesis, much less is known about the role of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD)
regulate the strength of synaptic transmission and the formation of new synapses in many neural networks. Therefore, we examined the
modulation of synaptic plasticity in the chronic mild stress animal model of depression.
in the hippocampal CA1 region by whole-cell patch clamp measurements in brain slices. Neurogenesis was assessed by doublecortin
Results: Exposure to chronic mild stress facilitated LTD and had no effect on LTP. Chronic application of the antidepressant fluvoxamine
impaired after chronic stress.
Conclusions: In addition to neurogenesis, long-term synaptic plasticity is an important and ubiquitous form of brain plasticity that is
disturbed in an animal model of depression. Facilitated depression of synaptic transmission might impair function and structure of brain
circuits involved in the pathophysiology of major depression. Antidepressants might counteract these alterations.
Key Words: Animal model, chronic mild stress, depression, fluvox-
amine, hippocampus, long-term synaptic plasticity, neurogenesis
portance, the pathophysiology of affective disorders and the
mode of action of antidepressants have been poorly understood.
In the last few years, evidence from preclinical and clinical
research has accumulated that brain plasticity might be disturbed
in depressed patients.
One prominent form of brain plasticity is adult neurogenesis
(Duman 2004; Lledo et al. 2006). Neural progenitor cells differ-
entiate to granule cells in the olfactory bulb and in the dentate
gyrus of the adult hippocampus (Altman and Das 1965; Gage
2000). Stress decreases adult neurogenesis (Gould et al. 1998),
whereas antidepressant treatment increases the formation of new
neurons and blocks the effects of stress (Czeh et al. 2001;
Malberg et al. 2000; Malberg and Duman 2003). It has been
postulated that functional neurogenesis is necessary for the
action of antidepressants in an animal model of depression and
anxiety (Santarelli et al. 2003). These preclinical findings might
reflect clinical evidence for hippocampal atrophy in mood
disorders (Bremner et al. 2000).
Despite these important findings, it has been questioned if
disturbed neurogenesis could account for all aspects of the
clinical course and the etiology of depression (Henn and Voll-
mayr 2004; Vollmayr et al. 2003). Reduced hippocampal volume
correlates with the total lifetime number of depressive episodes
but not with mood state (Videbech and Ravnkilde 2004). A recent
epression is a devastating disorder with high prevalence
and mortality, resulting in massive socioeconomic bur-
den (World Health Organization 2001). Despite its im-
study found a decreased neural stem cell proliferation in the
postmortem brains of patients with schizophrenia but not with
depression (Reif et al. 2006).
This has stimulated research on the role of other more
ubiquitous forms of brain plasticity in the etiology of depression.
Synapses underlie profound functional and morphological plas-
tic changes. Long-term synaptic plasticity regulates the strength
of synaptic transmission. Long-term potentiation (LTP) increases,
whereas long-term depression (LTD) decreases, synaptic trans-
mission (Linden 1999; Normann et al. 2000). Long-term potenti-
ation and LTD have been demonstrated in most brain regions of
rodents and also in slices from human brain (Chen et al. 1996). In
brain slices, long-term synaptic plasticity can be observed for
hours and in living animals it can be observed even for weeks or
months. Long-term synaptic plasticity is believed to be the
molecular basis of learning and memory (Bliss and Collingridge
1993; Kandel 2001). When efficiency changes of synaptic trans-
mission are consolidated, late phases of long-term synaptic
plasticity involve gene transcription, protein synthesis, and ulti-
mately synaptogenesis (Engert and Bonhoeffer 1999; Toni et al.
1999), finally leading to permanent morphological changes in the
synaptic structure of neuronal networks.
It has been proposed that long-term synaptic plasticity or its
modulation might be disturbed in depressed patients (Castrén
2005; Garcia 2002; Popoli et al. 2002; Spedding et al. 2003;
Stewart and Reid 2002). Different antidepressants and electro-
convulsive therapy have been shown to effectively modulate
synaptic plasticity in the dentate gyrus and the CA1 subfield of
the hippocampus and in the neostriatum (De Murtas et al. 2004;
Levkovitz et al. 2001; Shakesby et al. 2002; Stewart and Reid
2000; Von Frijtag et al. 2001).
We examined hippocampal long-term synaptic plasticity and
neurogenesis in the chronic mild stress (CMS) animal model of
depression (Willner et al. 1987; Willner 2005). The repeated
exposure of rodents to mild and unpredictable stressors has been
shown to produce behavioral changes that resemble certain core
features of human major depression. After CMS, animals show a
reduced sensitivity to reward. This anhedonic state can be
From the Department of Psychiatry (RH, KC, CN) and Institute of Physiology
Ltd (J-LM), Pharmaceuticals Division, Basel, Switzerland.
Address reprint requests to Dr. Claus Normann, Department of Psychiatry,
University of Freiburg, Hauptstr. 5, D-79104 Freiburg, Germany; E-mail:
Received May 24, 2006; revised July 13, 2006; accepted July 13, 2006.
BIOL PSYCHIATRY 2007;62:92–100
© 2007 Society of Biological Psychiatry
assessed by various behavioral paradigms such as reduced
preference for sucrose solutions (Willner et al. 1987), attenuated
place-preference conditioning (Papp et al. 1991), and reduced
intracranial self-stimulation behavior (Moreau et al. 1992).
Stressed animals showed a decrease in sexual activity (D’Aquila
et al. 1994) and grooming behavior resulting in a degradation of
the physical state of the fur (Griebel et al. 2002). Sleep architec-
ture was disturbed with rapid eye movement (REM) disinhibition
and fragmented sleep patterns (Moreau et al. 1995). Plasma
corticosterone levels were increased (Grippo et al. 2005). The
behavioral effects of CMS could be reversed by different classes
of antidepressants (Grippo et al. 2006; Moreau et al. 1992, 1994;
Muscat et al. 1992) and electroconvulsive therapy (ECT) (Moreau
et al. 1995) but not by antipsychotics (Moreau 1998; Papp et al.
1996). Recent work has demonstrated a suppression of neuro-
genesis in the hippocampal dentate gyrus of CMS-treated mice
and rats and a correlation of behavioral recovery and restored
neurogenesis after application of an antidepressant (Alonso et al.
2004; Jayatissa et al. 2006; Joels et al. 2004). The model has been
criticized, as the replication in some laboratories has turned out
to be difficult (Reid et al. 1997). Taken together, however, CMS
is an animal model of depression with high face validity (phe-
nomenological reproduction of signs and symptoms of the
disorder) and predictive validity (differentiation between effec-
tive and ineffective treatments).
By using the chronic mild stress protocol, we tested if
long-term synaptic plasticity is altered in experimentally de-
pressed animals and if this could be prevented by an antidepres-
Methods and Materials
Animals and Stress Protocol
Wistar Rats were used for all experiments. Adult rats were 2-
to 3-months-old (weight 350–450 g) and were housed in indi-
vidual cages with free access to food and water in a temperature-
(21°C) and light-controlled (12:12 hour light:dark cycle) environ-
ment. Juvenile rats (11–14 days postnatal) were used for some
The CMS protocol was applied at the Hoffmann-La Roche
research facility in Basel, Switzerland. Two-month-old rats were
subjected to a stress regimen for 3 weeks as described in Table 1
(adapted from Moreau et al. 1994). Restraint (R) consisted of
confinement to small (24 cm x 10 cm x 9 cm) cages for 1 hour.
One night of food and water deprivation (F/Wd) was immedi-
ately followed by exposure to restricted food for 2 hours (Fr,
scattering of 30 pellets of 20 mg in the cage). Another night of
water deprivation (Wd) was followed by exposure to an empty
bottle (Eb) for 1 hour. Other elements of the stress protocol were
overnight group housing in a soiled cage (GsC) and overnight
illumination (Oi). Moreover, the rats were maintained on a
reversed light/dark cycle (rLDC) from Friday evening to Monday
morning. The animals did not lose weight during the stress
protocol. When post-stress behavior was assessed by ventral
tegmentum self-stimulation (VTSS) in previous experiments from
the same laboratory, CMS proved to be very reliable in inducing
an increase in VTSS threshold in ?90% of all rats. The VTSS
threshold gradually returned to baseline values 10 to 20 days
after the termination of the stress regimen (Moreau et al. 1992,
Immediately after the end of the CMS protocol, five groups of
eight stressed and eight nonstressed animals each, which were
kept at identical conditions except the CMS treatment, were
consecutively transferred to the Department of Psychiatry, Uni-
versity of Freiburg, where the electrophysiological recordings
were performed within 8 days after the end of the stress protocol.
Electrophysiological experiments were done and analyzed in a
blinded manner: site staff was not aware if the rats had been
previously stressed or not. All protocols were approved by local
animal care committees in accordance with institutional guide-
Pharmacological Treatment and Plasma Levels
A group of 12 rats was treated with 20 mg/kg body weight
fluvoxamine (dissolved in Tween 80 .3% sodium chloride [NaCl])
(Sigma-Aldrich, Munich, Germany) administered by intraperito-
neal injection once daily for 21 days. In rats subjected to CMS (n
? 8), fluvoxamine was administered during the complete course
of the stress protocol. Control experiments with four stressed rats
injected with Tween 80 .3% NaCl once daily for 21 days revealed
no difference in the modulation of plasticity. Immediately after
decapitation, blood was taken from all rats treated with fluvox-
amine and plasma levels were measured by high-pressure liquid
chromatography. Plasma adrenocorticotropic hormone (ACTH)
and corticosterone levels were determined in a sample of six
stressed and six nonstressed rats by radioimmunoassay.
The animals were exposed to a pure oxygen atmosphere for
10 min and immediately afterward anesthetized by isoflurane
and killed by decapitation. The brain was removed and trans-
verse 350-?m hippocampal slices were cut using a vibratome
(DTK-1000; Dosaka, Kyoto, Japan). Slices were incubated at 34°C
for 20 min and subsequently held at room temperature. For
dissection, slicing, and storage, a solution containing 125 mmol/L
NaCl, 25 mmol/L sodium bicarbonate (NaHCO3), 32.5 mmol/L
glucose, 2.5 mmol/L potassium chloride (KCl), 1.25 mmol/L sodium
dihydrogen phosphate (NaH2PO4), 2 mmol/L calcium dichloride
(CaCl2), and 1 mmol/L magnesium dichloride (MgCl2) (equili-
brated with 95% O2/5% CO2) was used.
Slices were transferred to the recording chamber and super-
fused with saline solution containing 20 ?m picrotoxin to isolate
Table 1. The Chronic Mild Stress Protocol
MondayTuesdayWednesday ThursdayFridaySaturday Sunday
RRFr 2 hoursEb 1 hour
R, restraint; Oi, overnight illumination; F/Wd, food and water deprivation; Fr, food restriction; Wd, water depriva-
tion; Eb, exposure to empty bottle; GsC, group housing in soiled cage; rLDC, reversed light dark cycle. For details see
Methods and Materials.
R. Holderbach et al.
BIOL PSYCHIATRY 2007;62:92–100 93
excitatory neurotransmission. The CA1 pyramidal neurons were
identified visually and by their characteristic adaptation of the
firing pattern in response to a long depolarization. Infrared
differential contrast video microscopy was used (Axioskop 2 FS,
Zeiss; IMAGO-VGA, Till Photonics) (Zeiss, Göttingen, Germany.
Till Photonics, München, Germany). Patch pipettes were pulled
from borosilicate glass tubing (3–6 M?). For whole-cell record-
ings, pipettes were filled with a solution containing 115 mmol/L
K-gluconate, 20 mmol/L KCl, 10 mmol/L HEPES, 2 mmol/L
MgCl2, 10 mmol/L Na2-phosphocreatine, 4 mmol/L sodium aden-
osine triphosphate (NaATP), .3 mmol/L sodium guanosine 5’-
triphosphate (NaGTP), and 0 to .5 mmol/L ethyleneglycoltetrace-
tic acid (EGTA), equilibrated to pH 7.2. Recordings were made
with an EPC-9 amplifier (HEKA, Lambrecht, Germany). Bridge
balance was used to compensate the series resistance of 10 to 60
M?. Resting potentials were determined and the holding poten-
tial was set to -72 to -75 mV. To stimulate the Schaffer collateral
pathway, a 1- to 3-M? pipette filled with HEPES-buffered sodium
ion (Na?)-rich solution was placed in the stratum radiatum of the
CA1 region. Orthodromic stimulation was applied using 200-
?sec voltage pulses of 10 to 80 V at a frequency of .1 Hz
(Stimulator 2100, A-M Systems, Carlsborg, Washington). Stimula-
tion intensity was set to evoke an initial subthreshold excitatory
postsynaptic potential (EPSP) amplitude of 2 to 4 mV. Induction
protocols were started after recording of a stable EPSP baseline
for at least 10 min. A 500-msec current pulse leading to a
hyperpolarization of approximately 5 mV was applied with a
frequency of .01 Hz to continuously monitor input and series
resistance. Experiments were discarded when series resistance
exceeded 80 M?. Recordings were performed at 21°C to 23°C.
Signals were filtered at 5 Hz, digitized at 10 Hz, and stored
online. For data acquisition and analysis, Pulse and PulseFit
software (HEKA) were used.
Immunohistochemistry and Imaging of Neurogenesis
For doublecortin immunohistochemistry, we used 350-?m
thick hippocampal slices, which were obtained from the same
hemispheres as the slices for electrophysiological measurements.
One slice per animal was obtained from the same area in the
hippocampus from 5 stressed and 5 nonstressed rats. The slices
were fixed in 4% paraformaldehyde and washed. The tissue was
then incubated overnight at room temperature with the primary
antibody goat-anti-doublecortin (C-18, immunoglobulin G [IgG],
1:100; together with 5% donkey serum and .3% Triton X-100
Santa Cruz Biotechnology, Santa Cruz, California). Slices were
washed 3 times for 30 min in .1 mol/L phosphate buffered saline
(PBS) and the secondary antibody donkey-anti-goat-Alexa 568
(1:200, Invitrogen, Karlsruhe, Germany) was co-applied with .3%
Triton X-100 for 24 hours at 4°C. After rinsing in PBS, slices were
embedded in ProLong Antifade (Invitrogen).
Immunofluorescence was analyzed using a confocal laser-
scanning microscope (LSM 510, Zeiss). Confocal stacks with a
total thickness of 30 ?m were obtained and a projection image
was constructed. Stained cells were manually counted by a
blinded rater in the granule cell layer and the subgranular zone
of the dentate gyrus.
Data Analysis and Statistics
To calculate the mean EPSP amplitude to quantify synaptic
plasticity, 60 consecutive EPSPs were averaged in the last 10 min
before the start and 20 to 30 min after the termination of the
induction protocols. Changes of the mean EPSP amplitude pre
and post plasticity induction within an experimental series were
assessed by a Wilcoxon signed rank test. Differences between
separate series were analyzed by a Mann-Whitney test. A signif-
icance level of .05 was used. All values are given as mean ? SEM;
error bars in the figures also represent SEM. Average EPSP
amplitudes in amplitude-time plots represent means from four
consecutive EPSPs. GraphPad Prism software was used to aver-
age and plot EPSP amplitudes (GraphPad, San Diego, California).
Fitting of curves was done with Igor Pro Software (Wavemetrics,
Fluvoxamine was a gift of Solvay Pharmaceuticals, Weesp,
Netherlands. All other substances were from Sigma-Aldrich,
Munich, Germany or Merck, Darmstadt, Germany.
Chronic Mild Stress Inhibits Neurogenesis
in the Dentate Gyrus
Adult rats were subjected to 3 weeks of chronic mild stress
(Table 1) and examined 2 to 8 days later. To get an estimate on
the effects of the stress procedure on brain plasticity, neuro-
genesis in the dentate gyrus was assessed by immunohisto-
chemistry for doublecortin, which is expressed in newborn
hippocampal granule cells during the first 3 weeks after
mitosis (Brown et al. 2003). We found a significant decrease of
newly generated neurons after CMS (47.6 ? 3.0 labelled cells
in the nonstressed group vs. 20.2 ? 2.0 cells in the stressed
group in the 30 ?m projection image, p ? .01, n ? 5 each,
Figure 1). These results confirm previous findings of a stress-
induced inhibition of neurogenesis and demonstrate the effi-
cacy of the stress protocol.
Figure 1. Chronic mild stress impairs neurogenesis in the hippocampus.
Doublecortin immunostaining of newborn neurons in the dentate gyrus of
the adult rat hippocampus. Projection image from confocal stacks with a
94 BIOL PSYCHIATRY 2007;62:92–100
R. Holderbach et al.
Intrinsic Properties and Synaptic Function
We conducted whole-cell recordings of hippocampal CA1
pyramidal cells and first compared basic intrinsic membrane and
action potential (AP) properties and synaptic function in brain
slices from nonstressed and stressed adult rats (Table 2, Figure 2).
The membrane input resistance (RM) was calculated from the
current response to a hyperpolarizing pulse (-5 mV from mem-
brane potential of -70 mV for 50 msec). Membrane input
resistance was increased in stressed rats but this difference did
not reach significance. The membrane time constant tau was
estimated by fitting the voltage decay after a long hyperpolariz-
ing current pulse to a single exponential function. Tau was
nonsignificantly increased in stressed rats. Action potentials were
evoked by a short current injection into the postsynaptic neuron
(300–800 pA for 5 msec). The AP amplitude was unchanged,
whereas the AP half-width was significantly increased in slices
from CMS rats, indicating a downregulation of voltage-gated
potassium ion (K?) channels. The frequency of an AP train in
response to a long depolarizing pulse (300 pA for 400 msec) was
slightly but not significantly increased after stress. The properties
of EPSPs that were evoked by Schaffer collateral stimulation were
not significantly altered.
Facilitation of LTD After Chronic Mild Stress is Prevented
We then proceeded to examine the effects of CMS on
long-term synaptic plasticity. Long-term depression of synaptic
responses can be readily induced in hippocampal slices from
juvenile rodents by homosynaptic or associative protocols
(Mulkey and Malenka 1992; Normann et al. 2000). In the adult
hippocampus, however, induction of LTD is much more difficult.
It has been suggested that LTD might be developmentally
regulated and that non-N-methyl-D-aspartate (NMDA) receptor-
dependent pathways might play a more prominent role in adult
than in juvenile animals (Lee et al. 2005; Kemp et al. 2000; Xiong
et al. 2004). We used homosynaptic paired-pulse low frequency
stimulation (PP-LFS), an induction protocol that is known to
induce reliable LTD in juvenile hippocampus (Kemp and Bashir
Excitatory postsynaptic potentials were evoked by extracellu-
lar Schaffer collateral stimulation (Figure 3). In PP-LFS, 900 pairs
of subthreshold EPSPs were applied at 1 Hz with an interstimulus
interval of 50 msec. In nonstressed adult rats, this resulted in a
short-term depression for 5 to 10 min, which changed to a small
but significant long-term potentiation of synaptic transmission.
Excitatory postsynaptic potential amplitudes 20 to 30 min after
patch clamp recordings were made from CA1 pyramidal neurons in brain
slices from adult rats. Excitatory postsynaptic potentials were induced by
current stimulation of the Schaffer collateral pathway. Typical single exper-
iment in a brain slice from a stressed rat. Dots represent maximal EPSP
amplitudes. At the time indicated by an arrow, 900 pairs of subthreshold
paired-pulse low frequency stimulation). This resulted in a stable LTD. The
upper traces represent the paired-pulse induction paradigm and typical
EPSPs before and 20 min after induction of PP-LFS from the same experi-
ment. EPSP, excitatory postsynaptic potential; PP-LFS, paired-pulse low fre-
quency stimulation; LTD, long-term depression.
Table 2. Intrinsic Properties and Synaptic Function in the Hippocampal
CA1 Region of Nonstressed and Stressed Adult Rats
179.4 ? 15.8
n ? 22
22.7 ? 1.4
n ? 16
132.1 ? 1.7
n ? 5
1.84 ? .04
n ? 5
20.3 ? 3.1
n ? 18
16.5 ? .4
n ? 22
41.2 ? .7
n ? 22
192.8 ? 17.6
n ? 25
27.0 ? 1.8
n ? 20
131.3 ? .8
n ? 6
1.98 ? .02
n ? 6
20.9 ? 2.1
n ? 20
16.5 ? .3
n ? 25
42.6 ? .6
n ? 25
Membrane Time Constant
AP Amplitude (mV)
AP Half Width (msec)p ? .005
AP Frequency (Hz) ns
EPSP Rise Time (msec) ns
EPSP Half Width (msec)ns
RM, membrane input resistance; ns, nonsignificant; AP, action potential;
EPSP, excitatory postsynaptic potentials.
Figure 2. Intrinsic membrane properties and synaptic transmission. Repre-
sentative whole-cell measurements from single neurons in brain slices ob-
tained from adult rats after chronic mild stress (red traces) and control
exponential function to obtain the membrane time constant tau (green, fit
of a single pulse from a nonstressed rat; blue, stressed rat). (C) Action
in rats after CMS. (D) Train of action potentials evoked by a depolarizing
from 10 EPSPs in each cell. (F) Summary bar graph representing relative
changes between cells from nonstressed and stressed animals (membrane
tude and half width, frequency of action potential train, EPSP rise time
and half width). CMS, chronic mild stress; EPSP, excitatory postsynaptic
R. Holderbach et al.
BIOL PSYCHIATRY 2007;62:92–100 95
stimulation were increased to 111.7 ? 3.0% (n ? 6, p ? .005,
Figure 4A) of the averaged baseline EPSP amplitude. After
chronic mild stress, PP-LFS induced a significant LTD (82.5 ?
1.5%) of baseline EPSP amplitude (n ? 5, p ? .001, Figure 4B).
The effect of PP-LFS on synaptic transmission was significantly
different between nonstressed and stressed animals (p ? .001).
When rats were treated with the selective serotonin reuptake
inhibitor (SSRI) antidepressant fluvoxamine during exposure to
chronic mild stress, PP-LFS again resulted in a potentiation of
synaptic responses (122.1 ? 2.9% of baseline EPSP amplitude,
n ? 4, p ? .001, Figure 4C). The increased EPSP amplitudes after
chronic mild stress with fluvoxamine treatment were significantly
different from the reduced amplitudes after chronic mild stress in
the absence of an antidepressant (p ? .001) but not from the
potentiated responses in nonstressed animals (p ? .05). When
nonstressed animals were treated for 3 weeks with fluvoxamine,
average EPSP amplitudes were increased to 125.3 ? 2.9% of
baseline after PP-LFS (n ? 4, p ? .001, Figure 4D). These results
indicate that chronic mild stress facilitated the induction of LTD,
which could be prevented by an antidepressant.
LTP is not Affected by CMS but Increased
by Antidepressant Treatment
Next, we examined LTP induced by theta burst stimulation
(TBS-LTP) (Schmidt-Hieber et al. 2004). Five EPSPs were paired
with five postsynaptic action potentials at a frequency of 100 Hz.
Five of these pairings were repeated at 5 Hz, and five of the
resulting theta burst blocks were repeated at a frequency of .1 Hz
(Figure 5A, inset). The TBS-LTP protocol resulted in a stable LTP
of 168.9 ? 3.22% of the baseline EPSP amplitude (n ? 5, p ?
.001, Figure 5A). When identical experiments were repeated in
CMS-stressed animals, the magnitude of the synaptic potentiation
was unchanged (176.0 ? 2.4%, n ? 5, p ? .001, Figure 5B;
nonstressed vs. stressed group: p ? .1). Chronic treatment with
fluvoxamine significantly facilitated LTP induction both in non-
stressed rats (259.4 ? 7.0% of baseline, n ? 4, p ? .0001, data not
shown; nonstressed nontreated group vs. nonstressed fluvoxam-
ine-treated group: p ? .001) and in stressed animals (207.2 ?
6.1%, n ? 4, p ? .001, Figure 5C; stressed nontreated group vs.
stressed fluvoxamine-treated group: p ? .001, Figure 5D). Taken
together, these results show that chronic mild stress had no effect
on LTP, whereas chronic application of an antidepressant facili-
tated the induction of LTP.
No Acute Effects of Glucocorticoids or Fluvoxamine
Electrophysiological recordings were performed 2 to 8 days
after the end of the CMS protocol and after termination of antide-
pressant treatment. At that time, corticosterone concentrations
(nonstressed group: 21.2 ? 4.3 ng/mL, stressed group: 19.7 ? 3.0
ng/mL, n ? 6, ns) and ACTH levels (nonstressed group: 163 ? 17
pg/mL, stressed group 242 ? 32 pg/mL, n ? 6, ns) were not
significantly different between nonstressed and stressed animals,
suggesting recovery from the acute effects of stress. Fluvoxamine
could not be detected in any of the samples of previously
fluvoxamine-treated rats, indicating that the substance had been
metabolized after the end of the treatment period. This means
that neither increased adrenal steroids nor fluvoxamine had any
acute effect on the electrophysiological results from this series.
The results of this study demonstrate that long-term synaptic
plasticity is altered in an animal model of depression. After 3
weeks of chronic mild stress, the induction of LTD was facilitated
in adult rats, whereas LTP remained unchanged. The antidepres-
sant fluvoxamine prevented the facilitation of LTD and upregu-
lated the induction of LTP.
Figure 5. Theta-burst LTP is not affected by stress and facilitated by fluvox-
amine. (A) Long-term potentiation could be induced by theta-burst stimu-
lation in adult nonstressed animals. Inset: stimulation protocol, typical re-
cording of a theta-burst action potential pattern with downward voltage
artifacts marking the EPSP induction, series of five theta bursts. (B) Un-
changed effect of theta-burst pairing on LTP induction in rats after chronic
of LTP in stressed animals. (D) Effects of theta-burst LTP under different
experimental conditions. Long-term potentiation was significantly facili-
tated both in nonstressed and stressed animals after chronic application of
Figure 4. Facilitation of paired-pulse LTD by stress is prevented by an
antidepressant. (A) Paired-pulse low frequency stimulation in adult non-
stressed rats. Averaged maximal EPSP amplitudes from six different experi-
ments. Paired-pulse low frequency stimulation resulted in a small LTP.
PP-LFS in stressed rats treated with fluvoxamine during CMS. Long-term
depression is no longer facilitated. (D) Effects of PP-LFS under different
experimental conditions. (Con, no treatment; Fluvox, chronic intraperito-
bars, 3 weeks of chronic mild stress.) LTD, long-term depression; EPSP,
excitatory postsynaptic potential; LTP, long-term potentiation; PP-LFS,
paired-pulse low frequency stimulation; CMS, chronic mild stress.
96 BIOL PSYCHIATRY 2007;62:92–100
R. Holderbach et al.
Basic Membrane Properties
When examining basic membrane, action potential, and EPSP
properties, we found a slight modulation of different parameters
by chronic mild stress. Input resistance, membrane time con-
stant, and action potential frequency were increased without
reaching statistical significance, whereas the action potential
duration was significantly increased. The most likely common
explanation for these findings would be an inhibition of potas-
sium conductances. In CA1 pyramidal cells, short-term and
chronic application of corticosterone has been found to increase
the membrane time constant and the action potential frequency
and duration (Beck et al. 1994). Corticosteroids have been
shown to control the inward rectifier sodium/potassium current
in CA1 neurons (Karst et al. 1993). A slight increase in membrane
excitability might favor synaptic plasticity in principle; however,
as the extent of the modulation is relatively small, other mecha-
nisms might contribute to the observed effects on synaptic
plasticity after stress.
Modulation of Synaptic Plasticity by Stress
and its Mechanisms
Paired-pulse LFS has been described to induce LTD in young
but not in adult animals in extracellular recordings (Kemp and
Bashir 1997; Kemp et al. 2000). Under our conditions, the
paired-pulse protocol resulted in a short-term depression in
nonstressed adult animals. After 5 to 10 min, a small potentiation
of synaptic responses could be observed, probably due to Ca2?
signals compatible with LTP induction. In contrast, a stable LTD
could be induced in rats exposed to chronic mild stress.
Our results are in line with other groups who have shown a
modulation of synaptic plasticity by different forms of stress.
Acute stress facilitated hippocampal LTD and blocked LTP in
CA1 both in brain slices from stressed animals and in freely
moving rats (Shors et al. 1989; Xu et al. 1997). Chronic stress was
administered as repeated immobilization, exposure to an in-
truder, or variable unpredictable stress paradigms and resulted in
an impairment of LTP in different regions of the hippocampus
(Alfarez et al. 2003; Pavlides et al. 2002; Radecki et al. 2005). A
recent publication described a long-lasting (7 to 9 month)
modulation of synaptic plasticity after stress in CA1 (Artola et al.
2006). In contrast to other studies, we did not observe an
impairment of LTP after stress. This might be due to differences
in the stress protocols or, more importantly, different induction
paradigms for plasticity and recording conditions. We used
whole-cell patch clamp recordings in adult animals and an
associative theta burst induction for LTP. Temporal coincidence
between EPSPs and postsynaptic bursting is regarded as a
naturally occurring signal for synaptic plasticity in the hippocam-
pus (Hofman et al. 2002, Paulsen and Sejnowski 2000).
We did not control for the behavioral effects of the CMS
protocol, but the alterations in neurogenesis indicate that the
treatment was effective. In previous studies, CMS has been
shown to reliably increase the VTSS threshold in most animals.
However, if the stress protocol had not altered the behavioral
state in a subgroup of animals, this would have caused an
underestimation of the effects on plasticity.
The modulation of synaptic plasticity by acute stress is
thought to be dependent on the activation of glucocorticoid
receptors. Exogenously applied corticosterone mimicked the
effects of stress, whereas a selective glucocorticoid receptor
antagonist prevented the facilitation of LTD in vivo in the
hippocampal CA1 area (Xu et al. 1998). In brain slices from CA1,
activation of steroid receptors modulated glutamatergic neuro-
transmission, impaired LTP, and facilitated LTD (Coussens et al.
1997; Karst et al. 2005, Pavlides et al. 1996). A putative mecha-
nism by which corticosteroids could modulate synaptic plasticity
might be an increase in voltage-dependent Ca2?conductances
(Karst et al. 2000; Kerr et al. 1992). As amplitude and time course
of the intracellular calcium concentration are key regulators of
synaptic plasticity (Gnegy 2000; Linden 1999; Sjöström and
Nelson 2002), increased Ca2? influx through voltage-gated chan-
nels might therefore facilitate LTD and inhibit LTP (Krugers et al.
2005). Low corticosterone and ACTH levels at the time of
electrophysiological recordings 2 to 8 days after termination of
the stress procedure suggest that sustained effects of glucocorti-
coids persist even after the stress hormones have returned to
near baseline levels (Yang et al. 2004).
Another candidate to be responsible for the stress-induced
modulation of synaptic plasticity is the brain-derived neurotro-
phic factor (BDNF). There is a complex interaction between
stress, BDNF, and long-term synaptic plasticity. Brain-derived
neurotrophic factor messenger RNA (mRNA) levels were de-
creased after acute and chronic stress in the hippocampus
(Scaccianoce et al. 2003; Smith et al. 1995). Corticosterone
further reduced BDNF (Schaaf et al. 1998). Brain-derived neuro-
trophic factor effectively regulates long-term synaptic plasticity:
in CA1, LTD was attenuated, whereas LTP was promoted (Figu-
rov et al. 1996; Ikegaya et al. 2002). Induction of LTP and LTD,
on the other hand, was accompanied by corresponding changes
in the secretion of endogenous BDNF, as shown in the perirhinal
cortex and in primary cultures of hippocampal neurons (Aicardi
et al. 2004; Gärtner and Staiger 2002). Both glucocorticoids and
the BDNF-extracellular signal-regulated kinase (ERK)/mitogen-
activated protein (MAP)-kinase cascade may be involved in the
mechanism of CMS-induced modulation of synaptic plasticity.
Modulation of Synaptic Plasticity by Antidepressants
Whereas glucocorticoids and downregulation of BDNF have
been shown to promote stress-induced depression of synaptic
networks, antidepressants might prevent or reverse this effect. In
our study, chronic application of the SSRI fluvoxamine had a dual
effect: stress-induced facilitation of LTD was prevented and LTP
induction was increased both in stressed and nonstressed ani-
mals. Previous reports on the modulation of synaptic plasticity by
antidepressants have been controversial: desipramine and mian-
serine enhanced the expression of LTP in the dentate gyrus
(Levkovitz et al. 2001). Antidepressants reversed the effects of
acute and chronic stress on LTP and LTD in CA1 and at synapses
from the hippocampus to the prefrontal cortex (Rocher et al.
2004; Von Frijtag et al. 2001). Electroconvulsive stimulation
impaired the induction of long-term depression in the neostria-
tum (De Murtas et al. 2004). On the other hand, an inhibition of
LTP has been reported in CA1 and the dentate gyrus after
application of antidepressants (Massicotte et al. 1993; Shakesby
et al. 2002; Stewart and Reid 2000).
How do antidepressants exert their effect on synaptic plastic-
ity? Several putative mechanisms have been proposed. For
example, chronic antidepressant treatment may increase BDNF
mRNA (Nibuya et al. 1995), or antidepressants might block LTD
directly by inhibition of Ca2? influx (Deak et al. 2000) or
indirectly by elevating central serotonin (5-HT) levels (Normann
and Clark 2005; Normann et al. 2000). Antidepressants might,
therefore, be able to protect and/or to rescue the functional
integrity of neuronal circuitry from the effects of stress.
R. Holderbach et al.
BIOL PSYCHIATRY 2007;62:92–100 97
Neurogenesis and Synaptic Plasticity
In addition to synaptic plasticity in the CA1 region of the
hippocampus, we examined neurogenesis in the dentate gyrus
from the same animals by doublecortin immunohistochemistry.
Doublecortin is an endogenous protein associated with cytoskel-
etal microtubules in neuronal growth cones and is transiently
expressed for 2 to 3 weeks both in the cytoplasm and dendrites
of newly generated young neurons (Brown et al. 2003; Francis et
al. 1999). Doublecortin immunostaining should be suitable to
assess the effects of CMS on neurogenesis, as the method allows
quantification of net effects on the number of newly generated
neurons over an adequate time span of 2 to 3 weeks (Rao and
We found a substantial decrease of newborn neurons after
CMS. Our results confirm previous findings of reduced neuro-
genesis after acute and chronic stress (Duman 2004; Gould et al.
1998; Vollmay et al. 2003). Alonso et al. (2004) have recently
shown a reduction of neurogenesis after 7 weeks of CMS. It has
been shown before that chronic application of antidepressants
prevents or reverses the effects of stress on neurogenesis (Czeh
et al. 2001; Malberg et al. 2000; Malberg and Duman 2003;
Namestkova et al. 2005; Van der Hart et al. 2002). In the chronic
mild stress model, 4 weeks of escitalopram have both restored
behavioral deficits and neurogenesis (Jayatissa et al. 2006).
Two important forms of brain plasticity, neurogenesis and
long-term synaptic plasticity, are modulated by stress and anti-
depressants. Is there a link between the modulation of neuro-
genesis and synaptic plasticity? It has been shown that LTP is
facilitated in newborn neurons (Schmidt-Hieber et al. 2004).
Ablation of neurogenesis by cranial irradiation impaired LTP in
the perforant path-dentate gyrus synapse (Snyder et al. 2001).
Long-term potentiation, which was electrically induced in the rat
dentate gyrus in vivo, enhanced neurogenesis and survival of
newborn cells (Bruel-Jungerman et al. 2006). Nevertheless, neu-
rogenesis in the dentate gyrus and plasticity of the Schaffer
collateral-CA1 synapse, as examined in our study, are most likely
not functionally interconnected.
Modulation of neurogenesis and synaptic plasticity might
constitute two endpoints of the same signalling pathway induced
by stress and reversed by antidepressants. It is tempting to
suggest a crucial role for corticosteroids and BDNF in these
effects. As in synaptic plasticity, both corticosterone and BDNF
are involved in the signalling pathway required to induce
neurogenesis. Brain-derived neurotrophic factor increases neu-
ronal turnover, whereas elevated corticosterone levels attenuate
adult neurogenesis (Alonso et al. 2004; Cameron and Gould
1994; Sairanen et al. 2005). In learned helplessness, another valid
animal model of depression, neurogenesis was transiently re-
duced after stress induction, as in our study. Depression-like
behavior, however, did not fully correlate with the amount and
time course of neurogenesis, indicating the involvement of other
mechanisms (Vollmayr et al. 2003). Together with the findings of
our study, this supports the notion that alterations in neurogen-
esis, synaptic plasticity, and behavior might coincide after stress
but might not be functionally interconnected.
We have shown alterations of synaptic plasticity in an animal
model of depression, which can be prevented by an antidepres-
sant. A role for synaptic plasticity in the pathophysiology of
depression might help to understand core features of etiology,
phenotype, and treatment of major depression. An impaired
modulation of synaptic plasticity might be caused by increased
stress, high levels of adrenal steroids, and impaired monoamine
neurotransmission, all described as precipitating factors in many
depressed patients (Caspi et al. 2003; Gold et al. 2002; Iversen
2005). Synaptic depression has been shown to propagate
throughout a neural network (Fitzsimonds et al. 1997). A wide-
spread facilitation of synaptic depression might then impair the
integrity of neuronal circuits involved in mood and cognition,
causing the phenotype of major depression. Both rapid and
delayed modification of brain function could be explained by
synaptic plasticity. By regulating synaptogenesis, long-term syn-
aptic plasticity might finally cause morphological volume
changes in the brain, which were reported in depressed humans.
Antidepressants might exert their effect by reversing the alter-
ations of synaptic plasticity.
This study was supported by the Deutsche Forschungsgemein-
schaft (CN: DFG NO 370-3, JB: SFB-505). The authors declare no
conflict of interest.
We gratefully acknowledge the help of Dr. Christoph Schmidt-
Hieber with establishing techniques for whole-cell recording in
slices from adult animals. We wish to thank Professor Rainer
Landgraf, Max Planck Institute of Psychiatry, Munich, for deter-
mination of corticosterone plasma levels; Dr. H.W. Clement,
Department of Child and Adolescent Psychiatry, University of
Freiburg, for determination of fluvoxamine plasma levels; and
Fabien Delerue, Hofmann-La Roche, for technical help with the
CMS model. We are very grateful to Hofmann-La Roche for
providing chronic mild stressed rats and to Solvay Pharmaceu-
ticals for the donation of fluvoxamine.
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