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Neuropsychiatric Disease and Treatment 2018:14 1737–1746
Neuropsychiatric Disease and Treatment Dovepress
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http://dx.doi.org/10.2147/NDT.S163756
changes in synaptic plasticity are associated with electroconvulsive shock-induced learning and memory impairment in rats with depression-like behavior
Qibin chen1
li ren1
su Min1
Xuechao hao2
hengsheng chen3
Jie Deng1
1Department of anesthesiology, The First affiliated hospital of chongqing Medical University, chongqing, 2Department of anesthesiology, West china hospital of sichuan University, chengdu, sichuan, 3Ministry of education Key laboratory of child Development and Disorders, china international science and Technology cooperation Base of child Development and critical Disorders, chongqing Key laboratory of Pediatrics, chongqing, People’s republic of china
Background: Accompanied with the effective antidepressant effect, electroconvulsive shock (ECS) can induce cognitive impairment, but the mechanism is unclear. Synaptic plasticity is
the fundamental mechanism of learning and memory. This study aimed to investigate the effect
of ECS on synaptic plasticity changes in rats with depression-like behavior.
Methods: Chronic unpredictable mild stress procedure was conducted to establish a model of depression-like behavior. Rats were randomly divided into the following three groups: control
group with healthy rats (group C), rats with depression-like behavior (group D), and rats with
depression-like behavior undergoing ECS (group DE). Depression-like behavior and spatial
learning and memory function were assessed by sucrose preference test and Morris water test,
respectively. Synaptic plasticity changes in long-term potentiation (LTP), long-term depression
(LTD), depotentiation, and post-tetanic potentiation (PTP) were tested by electrophysiological
experiment.
Results: ECS could exert antidepressant effect and also induced spatial learning and memory impairment in rats with depression-like behavior. And, data on electrophysiological experiment
showed that ECS induced lower magnitude of LTP, higher magnitude of LTD, higher magnitude
of depotentiation, and lower magnitude of PTP.
Conclusion: ECS-induced learning and memory impairment may be attributed to postsyn- aptic mechanism of LTP impairment, LTD and depotentiation enhancement, and presynaptic
mechanism of PTP impairment.
Keywords: electroconvulsive therapy, learning, memory, synaptic plasticity, electrophysiology
Introduction Depression has been ranked as the third disease burden in the world, and .1 million
people commit suicide each year due to depression.1,2 Although antidepressants are the
first-line treatment for depression, approximately one-third of patients, especially with
major or refractory depression, are not responsive to the medication.3 Electroconvulsive
therapy (ECT) is conducted as the most effective treatment for those with major or
drug-resistant depression. Nevertheless, accompanied with its excellent treatment
effect, ECT can induce learning and memory impairment, which is a major limitation
in the clinical use of ECT.4 Unfortunately, the underlying mechanism of learning and
memory impairment induced by ECT is still poorly understood.
Persistent neural modifications are widely regarded as the cellular basis for learning
and memory.5 Synaptic plasticity is the fundamental mechanism of neural modifications,
correspondence: su Min Department of anesthesiology, The First Affiliated Hospital of Chongqing Medical University, No 1 Youyi road, Yuzhong District, chongqing 400016, People’s republic of china Tel/fax +86 23 8901 1068 email [email protected]
Journal name: Neuropsychiatric Disease and Treatment Article Designation: Original Research Year: 2018 Volume: 14 Running head verso: Chen et al Running head recto: Learning and memory impairment in rats with depression-like behavior DOI: 163756
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and synaptic plasticity supporting learning and memory
process involves persistent changes in synaptic efficacy
such as long-term potentiation (LTP) and long-term depres-
sion (LTD).6,7 Although LTP is remarkable for its stability,
accumulative evidence revealed that LTP could be reversed if
applied shortly after LTP induction and this form of synaptic
plasticity was named as depotentiation.8 Depotentiation has
been reported in hippocampus9,10 and other brain regions
closely related to learning and memory, such as prefrontal
cortex11 and amygdala.12 Thus, it is universally accepted that
LTP, LTD, and depotentiation conduct as opposing mecha-
nisms that maintain a dynamic range of synaptic efficacy and
keep synaptic homeostasis.13,14 Our previous study found that
electroconvulsive shock (ECS, an analog of ECT to animals)
could induce LTP impairment.15 However, whether LTD
or depotentiation contributes to ECT-induced learning and
memory impairment is still unknown.
Virtually, all synapses are mediated by short-lived and
long-lasting process. Thus, besides the long-term modifica-
tions of synaptic plasticity, changes in short-term synaptic
plasticity also have an important role in learning and memory.
Post-tetanic potentiation (PTP) is a widespread form of
short-term synaptic plasticity, which suggests that synaptic
efficacy is enhanced for tens of seconds to minutes after
high-frequency stimulation (HFS) with a train of hundreds
of pulses.16 Furthermore, it has been proved that presynaptic
transmitters’ release is reflected by PTP.17 Our previous study
found that ECS-induced learning and memory impairment
was attributed to imbalance of hippocampal Glu/GABA.18
However, it is still unclear whether PTP is involved in the
learning and memory impairment induced by ECT. Besides,
how transmitter release influences the learning and memory
function in the model of ECS necessitates further study.
In this study, using behavioral test and electrophysi-
ological experiments, we investigate the effects of ECS on
learning and memory as well as the potential roles of LTP,
LTD, depotentiation, and PTP in this process.
Methods animals Healthy adult male Sprague Dawley rats (weight 200–250 g,
aged 2–3 months) were obtained from the Laboratory Animal
Center of Chongqing Medical University. All rats were
housed at standard condition (temperature at 22°C±2°C, humidity at 62%±3%, and 12/12 h light–dark cycle) in the animal room. The rats were kept for 7 days acclimation
period before experiment. All experiment protocols were
approved by the Ethical Committee of the First Affiliated
Hospital of Chongqing Medical University (No 2017-004)
and conducted according to National Institutes of Health’s
Guild for the Care and Use of Laboratory Animals.
rats’ model of depression-like behavior As previously described, chronic unpredictable mild stress
(CUMS) procedure was conducted to establish a model of
depression-like behavior in rats.19 All rats except for those
in group C were housed in individual cages and exposed the
following stress: food deprivation for 24 h, water depriva-
tion for 24 h, continuous lighting for 24 h, tailing pinching
for 1 min, 5 min swimming in the cold water of 4°C, 5 min swimming in the hot water of 45°C, shaking for 20 min, damp sawdust for 24 h, and cages tilting to 45° for 24 h. To avoid habituation and provide an unpredictable feature
to the stressors, all the stressors were randomly scheduled
and repeated within 4 weeks.
experiment groups and treatment Rats were randomly divided into the following three groups:
group C includes the healthy rats without any treatment,
group D includes the depression-like behavior rats and treated
with sham ECS, and group DE includes the depression-like
behavior rats and treated with ECS. A total of 32 rats were
included for each group. ECS was conducted via bilateral
ear clip electrodes with a Niviqure ECS system (Nivique
Meditech, Bangalore, India) on the basis of following
parameters: bidirectional square wave pulses, 0.8 A in
amplitude, 1.5 ms in width, 125 Hz in frequency, and 0.8 s
in duration, and 120 mC charge. Sham ECS was conducted
as the same process with ECS but without currents. The ECS
or sham ECS was conducted once daily for 7 days.
sucrose preference test Sucrose preference test is widely accepted to test anhedo-
nia, which is one of the core symptoms of depression to
evaluate the depression-like behavior in rats. The test was
conducted as previously described.20 The test was com-
pleted within 72 h. In the first 24 h, rats were kept with two
bottles of 1% sucrose solution to adapt sucrose consump-
tion. In the second 24 h, rats were kept with one bottle of
1% sucrose solution and one bottle of sterile water. In the
third 24 h, after water and food deprivation for 23 h, all
rats were kept with two identical and preweighed bottles
for 1 h. One bottle was filled with 1% sucrose solution, and
another bottle was filled with sterile water. After 30 min
free drinking, the position of two bottles was exchanged
to prevent the position preference. The sucrose preference
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learning and memory impairment in rats with depression-like behavior
percentage (SPP) was calculated as the following formula:
SPP (%) = sucrose consumption (g)/(water consumption [g] + sucrose consumption [g]) × 100%.
Morris water maze It is well received that hippocampus-dependent spatial
learning and memory function of rats can be assessed by
Morris water maze.21 A circle pool (150 cm in diameter and
50 cm in height) was filled with water colored by black ink,
and a submerge platform (11 cm in diameter) was provided
below the surface of the water with ~1–2 cm. The pool was divided into four quadrants, and each rat was placed
into the water randomly at one of the four quadrants to find
the hidden platform within 60 s. If the rats did not find the
platform within 60 s, they were guided to the platform with
a stick and stayed on the platform for 15 s. Each rat was
placed into the water gently from four different quadrants
once a day for 5 consecutive days. The time to find the plat-
form for each quadrant was defined as escape latency, and
average time from four quadrants of the consecutive 5 day
was analyzed. On the sixth day, the platform was removed
and rats were placed into water to swim with a limitation
of 60 s. Space exploration time, defined as swimming time
in the platform quadrant of each rat, was recorded. Escape
latency, space exploration time, and swimming speed based
on the swimming track recorded by a video track system
program (Zhenghua Instruments, Anhui, China) were ana-
lyzed. A plain experimental timeline for all behavior tests
is shown in Figure 1A.
hippocampal slice preparation Rats were anesthetized by 2% pentobarbital sodium, and the
brain was removed gently. Hippocampal slices (400 μm thick) were cut by a vibratome (NVSLM1; WPI, Sarasota, FL, USA)
in 0°C–4°C cutting solution oxygenated with the mix gas of
95% O 2 and 5% CO
2 . Cutting solution was configured as
follows (in millimolar): 3 KCl, 1.25 NaH 2 PO
4 , 26 NaHCO
3 ,
0.4 vitamin C, 2 sodium pyruvate, 2 sodium lactate, 10 glucose,
220 sucrose, 1 MgCl 2 , 1 CaCl
2 , 1 MgSO
4 (pH 7.3–7.4; osmotic
pressure 300–310 mOsmol/L). Slices were incubated in a
chamber filled with oxygenated recording solution at 34°C for 60 min and then incubated in identical solution at 24°C for at least 60 min before recording. Recording solution was
comprised as follows (in millimolar): 124 NaCl, 3 KCl, 1.25
NaH 2 PO
4 , 26 NaHCO
3 , 0.4 vitamin C, 2 sodium pyruvate,
2 sodium lactate, 10 glucose, 1 CaCl 2 , 1 MgSO
4 (pH 7.3–7.4;
osmotic pressure 300–310 mOsmol/L).
electrophysiological experiment A single hippocampal slice was placed in the recording cham-
ber and was continuously perfused with oxygenated record-
ing solution. A bipolar stimulating electrode was placed in
the stratum radiatum of CA3 region, and a glass micropipette
(resistance 2–3 MΩ) filled with filtrated recording solution was placed in the stratum radiatum of CA1 region to record
the field excitatory postsynaptic potentials (fEPSPs). Stimula-
tion intensity to evoke baseline fEPSPs was set as ~50% of the intensity, which elicited the maximal response. As previ-
ously described, after 30 min stable baseline fEPSPs’ record-
ing, LTP was induced by an HFS with the parameter of 400
pulses at 100 Hz.22 To assess the magnitude of LTP, the mean
value for the slope of fEPSPs recorded at 20–40 min after
stimulation was calculated and expressed as a percentage
of the mean value of the initial baseline slope of fEPSPs.
Depotentiation was induced as previously described.23 After
successful LTP induction, the same slice received a low-
frequency stimulation (LFS) (900 pulses at 1 Hz) to induce
depotentiation (depotentiation = [percentage of potentiation after LFS −100] ×100/[percentage of potentiation before LFS −100]). For LTD induction, after stable baseline fEPSPs
1
CUMS Day
SPT MWM ECS SPT MWM
28 29 31 32 36 37 43 44 46 47 51
A
SPT ECS EP
1
CUMS Day
28 29 31 32 38 39
B
Figure 1 Time overview of the study. Notes: (A) The time schedule for behavior test. (B) The time schedule for electrophysiological experiment. Abbreviations: cUMs, chronic unpredictable mild stress; ecs, electroconvulsive shock; eP, electrophysiological experiment; MWM, Morris water maze; sPT, sucrose preference test.
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recording for 30 min, LTD was induced by a LFS (900 pulses
at 1 Hz).23 The calculation of LTD was similar as that of
LTP. All the poststimulation fEPSPs of LTP, depotentiation
and LTD were recorded for 60 min. PTP was induced as
previously described with minor modification.24 After 30 s
stable baseline fEPSPs recording, PTP was induced by an
HFS (400 pulses at 400 Hz) and the poststimulation fEPSPs
were recorded for 100 s. The mean value for the slope of
fEPSPs recorded at 5 s after stimulation was calculated, and
PTP was expressed as a percentage of the mean value of the
initial baseline slope of fEPSPs. All electrophysiological data
were recorded and analyzed by Axon Instruments system
(MultiClamp 700B amplifier, Digidata 1200 transverter,
pCLAMP 9.2 software; Molecular Devices LLC, Sunnyvale,
CA, USA). A scheduled timeline for electrophysiological
experiment is shown in Figure 1B.
statistical analysis Statistical analysis was performed with SPSS (Version 17.0;
SPSS Inc., Chicago, IL, USA). All data were expressed
as mean ± SD. Statistical significance was determined by repeated measures analysis of variance (data of escape latency
from Morris water maze). The other data were analyzed by
one-way analysis of variance, followed by Bonferroni cor-
rection to compare differences between the groups. P,0.05
was considered statistically significant.
Results along with the antidepressant effect, ecT- induced learning and memory impairment First, we want to clear the effect of ECS on behavior
changes. Eight rats in each group were used to behavior test.
Depression-like behavior was tested by sucrose preference
test. As shown in Figure 2A, group D and group DE shown
lower SPP than group C after CUMS procedure (F=42.102, post hoc test, P,0.001 and ,0.001, respectively). After ECS
treatment, SPP of group DE was higher than that of group D
(F=36.695, post hoc test, P,0.001); however, it showed no difference compared with group C (post hoc test, P=0.810). Spatial learning and memory function was tested by Morris
water maze. There was no difference in the comparison of
swimming speed for each group (data were not shown).
Escape latency decreased gradually during the 5 days training
for the three groups. However, rats in group DE spent more
C
#
60
50
40
20
30
10
0 C D DE
Groups
Sp ac
e ex
pl or
at io
n tim
e (s
)
*
*
Group DE
100 A B
60
40
#
20
0
80
60
40
20
0 Before treatment
Su cr
os e
pr ef
er en
ce pe
rc en
ta ge
Es ca
pe la
te nc
y (s
)
After treatment
Days 0 1 2 3 4 5
*
*,#
* * *
Group C Group D Group DE
Group C Group D
Figure 2 effects of ecs on depression-like behavior (A) and spatial learning and memory function (B and C). Notes: Sucrose preference percentage is the test index of sucrose preference test, and lower sucrose preference percentage indicated more significant depression-like behavior. escape latency and space exploration time are the test index of Morris water maze, and longer escape latency and shorter space exploration time indicated worse learning and memory performance. group c, control group with healthy rats; group D, rats with depression-like behavior; group De, rats with depression-like behavior undergoing ecs. *P,0.05 compared with group c; #P,0.05 compared with group D. Abbreviation: ecs, electroconvulsive shock.
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learning and memory impairment in rats with depression-like behavior
time to find the platform than other two groups (F=111.803, post hoc test, P,0.001 and ,0.001, respectively). Further-
more, escape latency of group D was longer than that of
group C (post hoc test, P=0.001) (Figure 2B). Data of space exploration time suggested that group DE spent least time
to swim in the platform quadrant (F=17.394, post hoc test, P,0.001 and 0.027, respectively). What is more, group D
showed shorter space exploration time than group C (post
hoc test, P=0.004) (Figure 2C).
ecs-induced lTP impairment and depotentiation enhancement To illuminate the underlying electrophysiological mecha-
nisms of learning and memory impairment induced by ECS,
LTP and depotentiation were assessed. Morris water maze
itself was a process of learning and memory. To prevent
the potential effect of Morris water maze on subsequent
electrophysiological assessment, another eight rats in each
group were included. As shown in Figure 3, baseline fEPSP
of group DE (fEPSP slope, 0.206±0.196, F=85.683, post hoc test, P,0.001) was higher than that of group C and group D.
No difference was found in the comparison of baseline
fEPSP between group C (fEPSP slope, 0.118±0.014) and group D (fEPSP slope, 0.100±0.009, post hoc test, P=0.053), although the baseline fEPSP was lower in group D. For LTP
test, group DE (normalized fEPSP slope, 129%±4%) showed lower magnitude of LTP than group D (normalized fEPSP
slope, 166%±5%, F=119.934, post hoc test, P,0.001) and group C (normalized fEPSP slope, 184%±8%, post hoc test, P,0.001). Compared with group C, the magnitude of
LTP was lower in group D (post hoc test, P,0.001). For
depotentiation test, ~50% LTP was reversed by LFS in group C (normalized fEPSP slope, 42%±7%). Compared with group C, depotentiation was enhanced in group D
(normalized fEPSP slope, 69%±5%, F=83.438, post hoc test, P,0.001) and group DE (normalized fEPSP slope,
89%±5%, post hoc test, P,0.001). Furthermore, group DE exhibited stronger depotentiation than group D (post hoc
test, P,0.001).
ecs-induced lTD enhancement LTD is another important form of synaptic plasticity and
also plays a central role in learning and memory. In our
experiment, group DE (normalized fEPSP slope, 58%±5%) exhibited higher magnitude of LTD compared with group D
(normalized fEPSP slope, 68%±7%, F=12.438, post hoc test, P=0.025) and group C (normalized fEPSP slope, 77%±7%,
post hoc test, P,0.001). What is more, compared with
group D, the magnitude of LTD was lower in group C (post
hoc test, P=0.025) (Figure 4).
ecs-induced PTP impairment LTP, LTD, and depotentiation are forms of postsynaptic
plasticity; however, we wanted to clear whether presynaptic
plasticity, such as PTP, was related to the learning and
memory impairment induced by ECS. As shown in Figure 5,
the magnitude of PTP of group DE (normalized fEPSP slope,
121%±9%) was lower than that of group C (normalized fEPSP slope, 150%±7%, F=23.927, post hoc test, P,0.001) and group D (normalized fEPSP slope, 140%±5%, post hoc test, P,0.001). Compared with group C, the magnitude of
PTP was lower in group D (post hoc test, P=0.034).
Discussion The present study confirmed that along with the antidepres-
sant effect, ECS induced learning and memory impairment
in the rats’ model of depression-like behavior. ECS induced
synaptic plasticity changes including LTP impairment, LTD
and depotentiation enhancement, and PTP impairment in
rats with depression-like behavior, leading to learning and
memory impairment.
It has been proved that measures, such as learned
helpless,25 olfactory bulbectomy,26 maternal separation,27 and
CUMS,28 can induce depression-like behavior of rats. In our
study, depression-like behavior model was constructed by
CUMS because this model can better simulate the process
of the depression induced by environmental stress, which is
one of the most common pathogeneses of depression.29 Anhe-
donia is one the central symptoms of depression and can be
assessed by SPP for rats. In line with other study,30 our results
revealed that SPP decreased significantly after CUMS proce-
dure and ECS increased the SPP in depression-like behavior
model of rats. Additionally, we found that ECS could increase
the baseline fEPSP, which was defined as “LTP-like” changes
and considered as the underlying mechanism of antidepres-
sant of ECS.31,32 The trend of baseline fEPSP was consistent
with the results of SPP, indicating successful model construc-
tion and antidepressant effect of ECS.
In Morris water maze test, we found rats with depression-
like behavior undergoing ECS exhibited learning and
memory impairment. LTP and LTD are two common electro-
physiological forms of synaptic plasticity. In our experiment,
we found that ECS induced LTP impairment. In the test of
LTD, to our surprise, the magnitude of LTD in group DE was
larger than that in group D, indicating that ECS induced LTD
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enhancement. Briefly, ECS induced LTP inhibition and LTD
enhancement. Accumulative evidence suggested that LTD or
LTP induction could be influenced by the history of synaptic
activity. This form of regulation of synaptic plasticity has
been named as “plasticity of plasticity” or “metaplasticity”,
which reveals that prime synaptic activation will suppress
subsequent LTP and facilitate LTD via LTD/LTP threshold
sliding to right.33 In the present study, ECS could induce
A
300
200
fE PS
P sl
op e
(p er
ce nt
ag e
of b
as el
in e)
100
0 –30 –20 –10 0 10 20 30 40 50
Time (min)
100 Hz, 400 pulses 1 Hz, 900 pulses
60 70 80 90 100110 120130140
Group C
1 2 3 B
300
200
fE PS
P sl
op e
(p er
ce nt
ag e
of b
as el
in e)
100
0 –30 –20 –10 0 10 20 30 40 50
Time (min)
100 Hz, 400 pulses 1 Hz, 900 pulses
60 70 80 90 100 110 120130 140
Group D
1 2 3
C
300
200
fE PS
P sl
op e
(p er
ce nt
ag e
of b
as el
in e)
100
0 –30 –20 –10 0 10 20 30 40 50
Time (min)
100 Hz, 400 pulses 1 Hz, 900 pulses
60 70 80 90 100 110 120 130 140
Group DE
1 2 3 D
0.3
0.2
0.1
0.0 C D DE
Groups
B as
el in
e fE
PS P
sl op
e (m
V/ m
s) *
E 250
200
150
100
50
0 C D DE
Groups
fE PS
P sl
op e
(p er
ce nt
ag e
of b
as el
in e)
*
* #
F 100
80
60
40
20
0 C D DE
Groups
fE PS
P sl
op e
(p er
ce nt
ag e
of re
ve rs
al )
*
* #
Figure 3 effects of ecs on lTP and depotentiation. Notes: Baseline fePsPs were recorded for 30 min, and poststimulation fePsPs of lTP and depotentiation were recorded for 60 min. (A–C) lTP and depotentiation were recorded in each group. Original traces of fePsP were recorded, and baseline trace (trace 1), post-hFs trace (trace 2), and post-lFs trace (trace 3) were exhibited. scale bar was set as 5 ms for the horizontal line and 1 mV for the vertical line. statistical analysis of baseline fePsP (D), lTP (E), and depotentiation (F) for different groups. group c, control group with healthy rats; group D, rats with depression-like behavior; group De, rats with depression-like behavior undergoing ecs. *P,0.05 compared with group c; #P,0.05 compared with group D. Abbreviations: ECS, electroconvulsive shock; fEPSPs, field excitatory postsynaptic potentials; LTP, long-term potentiation; LFS, low-frequency stimulation; HFS, high- frequency stimulation.
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learning and memory impairment in rats with depression-like behavior
baseline fEPSP increase, indicating synaptic activation
by ECS.31 And, our previous study also found that ECS
could upregulate the expression of pT305-CaMKII, which
is closely related to LTD/LTP threshold regulation.34 All
these results strongly suggested that ECS-induced learning
and memory impairment could not be simply explained by
synaptic plasticity. To the best of our knowledge, alternation
of regulatory capacity of synaptic plasticity or metaplasticity
contributes to learning and memory impairment induced by
ECS indeed.35
In our study, it was confirmed that rats with depression-
like behavior also exhibited learning and memory impairment
coincided with LTP impairment and LTD enhancement. Thus,
it is eligible to receive that learning and memory impairment
induced by depression and ECS involved in the regulation
of metaplasticity. In addition, our results revealed that more
serious LTP impairment and LTD enhancement were found
in group DE. In consideration of previous finding that stress
could induce LTP impairment and LTD enhancement,35,39 a
reasonable explanation is that stress of different intensities
induces different magnitudes of LTP impairment and LTD
enhancement. Acute strong enough stress, such as electronic
stimulation with ECS, will induce serious LTP impairment
and LTD enhancement; however, chronic or mild stimulation,
Figure 4 effects of ecs on lTD. Notes: Baseline fePsPs were recorded for 30 min, and poststimulation fePsPs were recorded for 60 min. (A–C) lTD was recorded in each group. Original traces of fePsP were recorded, and baseline trace (trace 1) and poststimulation trace (trace 2) were exhibited. scale bar was set as 5 ms for the horizontal line and 1 mV for the vertical line. (D) statistical analysis of lTP for different groups. group c, control group with healthy rats; group D, rats with depression-like behavior; group De, rats with depression- like behavior undergoing ecs. *P,0.05 compared with group c; #P,0.05 compared with group. Abbreviations: ECS, electroconvulsive shock; fEPSPs, field excitatory postsynaptic potentials; LTD, long-term depression; LTP, long-term potentiation.
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chen et al
such as CUMS procedure, will induce less LTP impairment
and LTD enhancement.
Except LTP and LTD, depotentiation is another important
form of synaptic plasticity but has often been neglected.
It has been proved that depotentiation and LTD contribute to
subserving forgetting.8,23 However, what should be stressed is
that depotentiation and LTD are two related but distinct forms
of synaptic weakening due to different specific pathways for
LTD and depotentiation.40,41 In our study, depotentiation was
enhanced in group DE, indicating that LTP was not stable
and could be easily reversed with ECS administration. As far
as we know, this is the first time to confirm that depoten-
tiation is responsible for learning and memory impairment
induced by ECS. Combined with aforementioned findings,
ECS-induced learning and memory impairment is mediated
by metaplasticity and depotentiation. It is well received that
either metaplasticity or depotentiation depends on NMDA
receptors.42 What is more, previous research found the
Figure 5 effects of ecs on PTP. Notes: Baseline fePsPs were recorded for 30 s, and poststimulation fePsPs were recorded for 60 s. (A–C) PTP was recorded in each group. Original traces of fePsP were recorded, and baseline trace (trace 1) and poststimulation trace (trace 2) were exhibited. scale bar was set as 5 ms for the horizontal line and 1 mV for the vertical line. (D) statistical analysis of PTP for different groups. group c, control group with healthy rats; group D, rats with depression-like behavior; group De, rats with depression- like behavior undergoing ecs. *P,0.05 compared with group c; #P,0.05 compared with group D. Abbreviations: ECS, electroconvulsive shock; fEPSPs, field excitatory postsynaptic potentials; PTP, post-tetanic potentiation.
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1745
learning and memory impairment in rats with depression-like behavior
intracellular signaling pathway of NMDA receptor, such as
mitogen-activated protein kinase (MAPK) involved in the
LTP, LTD, and depotentiation, although different specific
pathways for different types of synaptic plasticity (Ras-
Erk1/2 for LTP, Rap1-p38 for LTD, and Rap2-JNK for
depotentiation).41 It is reasonable to speculate that NMDAR
and its downstream proteins, such as MAPK, play an impor-
tant role in ECS-induced learning and memory. However, it
still needs further study to clarify how ECS induces learning
and memory impairment via regulating NMDA receptors’
function and MAPK signaling.
LTP, LTD, and depotentiation are long-term synaptic
plasticities. Accumulative evidence suggested that short-term
synaptic plasticity also involved the process of learning and
memory.43 Unlike long-term synaptic plasticity, short-term
synaptic plasticity, such as PTP, mainly reflects presynaptic
transmitter quanta release.17 In our previous studies, Luo et al18
found that ECS induced glutamate decrease in hippocampus.
Furthermore, Zhu et al44 found that ECS downregulated the
expression of GLT-1 (a type of glia glutamate transporters),
which induced glutamate accumulation in the synaptic cleft. It
is reasonable to speculate that transmitter release will decrease
after ECS. In the present study, we found that PTP was impaired
in group DE, which reflected a decrease in the probability of
glutamate release of available quanta. These results confirmed
our aforementioned assumption and demonstrated that learning
and memory impairment induced by ECS is mediated partly
by PTP impairment or glutamate release decrease.
It has been reported that anesthetics, such as propofol,
thiopental could alleviate the ECS-induced learning and
memory impairment.36,37 However, a previous study found
that anesthetics might influence the antidepressant of ECS.38
How to alleviate ECS-induced learning and memory impair-
ment without antidepressant efficacy compromise needs to
be further investigated. Also, several limitations exit in this
study. First, male rats were only included in this experiment
due to the effects of estrogen on the learning and memory,
so the results cannot extend to females. Second, the synaptic
plasticity changes were explored to illuminate the underlying
mechanism of ECS-induced learning and memory impair-
ment; however, the time-related changes in ECS were not
investigated in this study.
Conclusion Our study demonstrates that ECS induces various synaptic
plasticity changes, which involve both presynaptic and
postsynaptic mechanisms. Postsynaptic LTP impairment,
LTD and depotentiation enhancement, and presynaptic PTP
impairment possibly contribute to learning and memory
impairment induced by ECS.
Acknowledgments The authors are most grateful to Jingyuan Chen, PhD, of
the Department of Anesthesiology of The First Affiliated
Hospital of Chongqing Medical University, Chonqing, China,
for providing useful suggestions in this article. This work was
supported by the National Natural Science Foundation of
China grant (No 81271501), as well as a grant from National
Key Clinical Specialty Construction Project (No 2011-170)
and Chongqing Medical Key Discipline Construction Project
(No 2007-2).
Disclosure The authors report no conflicts of interest in this work.
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