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1. INTRODUCTION
Mood disorders are among the most common forms of
mental illness and are a leading cause of suicide.1) Although
chemical antidepressants such as selective serotonin or nor-
epinephrine reuptake inhibitors (SSRIs, SNRIs, respectively)
are widely prescribed, therapeutic responses to these treat-
ments require weeks and are realized in only a subset (ap-
proximately 60—70%) of patients.2) For many patients who
do not respond to such drugs, electroconvulsive seizure
(ECS) therapy is a highly effective and rapid alternative treat-
ment.3,4) However, the exact mechanisms underlying the ac-
tions of ECS therapy are not yet understood. Thus, identifica-
tion of the relevant therapeutic actions of ECS treatments
could lead to faster-acting and more effective therapies than
currently available chemical antidepressants.
In this review, I focus on molecular and cellular changes
induced by ECS models in several brain regions, particularly
the hippocampus, and consider the involvement of ECS in
behavioral actions and its potential for finding new therapeu-
tic targets in depression.
2. ECS-INDUCED GENE REGULATION AND NEURO-
GENESIS IN HIPPOCAMPUS
Recent Advances The molecular effects of ECS are di-
verse and include changes in levels of neurotransmitters,
gene expression, synaptic remodeling, and cell proliferation
(Fig. 1A). During the last 10 years, extensive studies have in-
vestigated molecular and cellular changes induced by ECS in
the hippocampus including gene regulation and neurogene-
sis. This section will provide a brief summary of these topics.
Regulation of Gene Expression in Hippocampus by
ECS Treatment Recent studies for identification of the
relevant actions of antidepressant treatments including ECS
have focused on intracellular signal-transduction pathways
and analysis of target genes.5—7) These alterations are
thought to mediate long-lasting changes in cell morphology
and function to underlie the action of antidepressants in part.
ECS treatment is the most robust gene inducer among all
antidepressant treatments especially in the hippocampus.
Among those genes, induction of neurotrophic/growth fac-
tors has been extensively studied. These are the brain-derived
neurotrophic factor (BDNF) and other growth factors such as
vascular endothelial growth factor (VEGF) and fibroblast
growth factor (FGF)-2.8—10)
BDNF, a member of the nerve growth factor family, has
been shown to increase synaptic strength, survival, and
growth of mature neurons through activation of a transmem-
brane receptor, TrkB. Expression of BDNF and TrkB is regu-
lated by short- and long-term ECS treatment.8) A single ECS
treatment results in 10—20-fold induction of BDNF gene
after ECS in rat hippocampal dentate gyrus. Long-term ECS
treatment (once daily for 7—10 d) also induces BDNF
mRNA. The extent of induction is decreased relative to the
level of that observed after a single induction. However, the
level of BDNF mRNA remains increased for a longer time
after long-term ECS compared with a single ECS treatment.
VEGF and FGF-2 mRNA in rodent hippocampus is also
increased after acute and chronic ECS treatment.9,11) These
factors were originally found mitogenic factors for non-neu-
ronal cells such as endothelial cells and fibroblasts, but now
they are also accepted as neurotrophic and neuroprotective
factors.12)
Administration of neurotrophic/growth factors directly
into the hippocampus or lateral ventricles has been shown to
mimic antidepressant effects in animal models. For instance,
infusions of BDNF into the hippocampus decrease immobil-
ity time in the forced swim test similar to the behavioral
effects of antidepressants.13) Infusions of VEGF into the
lateral ventricles mimic the action of antidepressants in mul-
tiple behavioral models.11) These findings indicate that neu-
rotrophic/growth factors are strong candidates to mediate
antidepressant effects by ECS treatment, at least in part.
ECS treatment also increases expression of several neuro-
peptide molecules such as neuropeptide Y (NPY), thyro-
Exploration of New Molecular Mechanisms for Antidepressant
Actions of Electroconvulsive Seizure
Eri SEGI-NISHIDA
Department of Systems Bioscience for Drug Discovery, Graduate School of Pharmaceutical Sciences,
Kyoto University; Sakyo-ku, Kyoto 606–8501, Japan.
Received February 22, 2011
Electroconvulsive seizure (ECS) therapy is a clinically proven treatment for depression and is often effective
even in patients resistant to chemical antidepressants. However, the molecular mechanisms underlying the thera-
peutic efficacy of ECS are not fully understood. Here, I review studies that show molecular, cellular, and behav-
ioral changes by ECS treatment, and discuss the functions of ECS to underlie the action of antidepressant ef-
fects. In hippocampus, these changes cover gene induction, increased adult neurogenesis, and electrophysiologi-
cal reactivity. Especially, the role of vascular endothelial growth factor (VEGF) in neurogenesis is discussed.
Among other gene expression changes in hippocampus, a role of cyclooxygenase (COX)-2, an inducible type of
the rate-limiting enzyme of prostanoid synthesis, is focused. ECS-induced changes in other brain regions such as
prefrontal cortex and hypothalamus, and ECS-induced behavioral changes are also reviewed. Understanding the
molecular, cellular, and behavioral changes by ECS will provide a new view to find potential targets for novel
antidepressant design that are highlighted by these findings.
Key words antidepressant; electroconvulsive seizure; hippocampus; gene expression; neurogenesis; cyclooxygenase
July 2011 939Biol. Pharm. Bull. 34(7) 939—944 (2011)
Review
© 2011 Pharmaceutical Society of Japane-mail: eri.segi.nishida@pharm.kyoto-u.ac.jp
tropin-releasing hormone (TRH), and VGF.9,10) Increase of
NPY mRNA in the hippocampus was observed especially
after chronic ECS treatment. The antidepressant-like effects
of NPY have been studied. In the forced swim test, acute ad-
ministration of NPY into the lateral ventricles produced an
antidepressant effect in naïve rodents.14) In addition, in the
learned helplessness model, acute infusion of NPY in the
CA3 of the hippocampus produced an antidepressant-like ef-
fect.15) TRH mRNA increases occurred only after chronic
ECS in the hippocampus. This increase is consistent with the
ability of ECS to increase prepro-TRH peptides in several rat
brain regions and with the antidepressant-like effects of TRH
in the rodent forced swim test.16) VGF is a neuropeptide pre-
cursor with a restricted pattern of expression in the central
nervous system.17) VGF was originally identified on the basis
of its rapid and robust regulation by nerve growth factor in
PC12 cells,18) and other stimuli such as exercise and neuronal
activity also induce VGF mRNA in a subset of neurons. Ex-
pression of VGF mRNA is increased by both acute and
chronic ECS in the dentate gyrus of the hippocampus. Single
infusion of VGF C-terminal peptide such as TLQP-62 and
AQEE-30 into the hippocampus of mice produces anti-
depressant-like effects in the forced swim test and tail sus-
pension test.19,20)
ECS treatment also changes the expression of various
genes including signaling molecules such as Grb2, Wnt-2,
and activin beta, several activity-induced immediate early
genes, and arachidonic acid pathway molecules including cy-
clooxygenase (COX)-2 in rodent hippocampus.9,10) Among
them, I will focus on COX-2, a critical enzyme of prostanoid
production, in a later section and discuss a role of COX-2
products in the hippocampus (Fig. 1B).
Increased Neurogenesis in Hippocampus by ECS Treat-
ment It is now clear that neuronal cell birth or neurogene-
sis occurs in the adult dentate gyrus region of the hippocam-
pus in most animals including humans (Fig. 2A). Moreover,
neurogenesis in the adult brain is a dynamic process that is
regulated by a variety of stimuli. A great deal of attention
was given that all classes of antidepressants including ECS
increase hippocampal cell proliferation and neurogenesis
(Fig. 1C).21,22) Since blockade of cell proliferation by irradia-
tion blocked the actions of antidepressants in the novelty-
suppressed feeding and the chronic unpredictable stress para-
digms,23) it is suggested that induction of neurogenesis is re-
940 Vol. 34, No. 7
Fig. 1. ECS Induces Rapid and Delayed Changes at Multiple Levels in the
Hippocampus
(A) Diagram of ECS-induced changes in the hippocampus. (B) A single ECS treat-
ment rapidly induces c-fos-IR (IR, immunoreactivity; brown) and cyclooxygenase
(COX)-2 mRNA expression (blue) in the dentate gyrus of hippocampus. (C) Multiple
ECS treatment gradually increase cell proliferation and number of immature neurons in
subgranular zone (SGZ), which borders the hilus and granular cell layer of the dentate
gyrus. Immunohistochemistry of bromodeoxy uridine (BrdU), which is incorporated
into DNA of dividing cells, is indicated with arrows. Immunohistochemistry of dou-
blecortin (DCX) is shown as a marker of immature neurons. Scale bars100
m
m (per-
formed by Y. Imoto, M. Sukeno and E. Segi-Nishida).
Fig. 2. Neurogenesis in the Adult Hippocampus
(A) Diagram of the stages of neurogenesis in the dentate gyrus. Resident neural stem
cells proliferate in the subgranular zone and form daughter progenitor cells. Proliferat-
ing cells differentiate into immature neurons and migrate into the granular cell layer
where they continue to mature. (B) Model of increased cell proliferation by ECS treat-
ment. ECS increases VEGF expression and its signaling, thereby leading to induction
of neural stem cell proliferation. Induction of neural progenitor cell proliferation may
occur via asymmetric division of neural stem cells or via direct effects of VEGF signal-
ing on progenitor cells. This contrasts with the induction of neural progenitor cell pro-
liferation, but not stem cell proliferation, in response to chronic fluoxetine administra-
tion. SGZ, subgranular zone; GCL, granular cell layer.
quired for antidepressant action, at least in part.
Interestingly, ECS is a more potent stimulator of prolifera-
tion than chemical antidepressants.24) ECS increases cell pro-
liferation by 2.5—4 fold compared with about 1.5 fold for
chemical antidepressants. In addition, while the neurogenic
action of antidepressants requires chronic treatment (14—
21 d), ECS can start neurogenic action within 3 d after a sin-
gle seizure.12) Two major subclasses of proliferating cells in
the subgranular zone (SGZ) in the dentate gyrus have been
characterized: neural stem cells and neural progenitor cells
(Fig. 2A). Segi-Nishida et al.25) showed that ECS increases
proliferation of neural stem cells at an early mitotic phase
then increases that of neural progenitor cells at a later phase
in SGZ of the hippocampus (Fig. 2B). On the other hand, it
was reported that chronic administration of the SSRI fluoxe-
tine only increases proliferation of neural progenitor cells in
the hippocampus without affecting neural stem cell prolifera-
tion.26) This accounts for the superior efficacy of ECS of hip-
pocampal cell proliferation and neurogenesis. The relation
between the superior efficacy of ECS of hippocampal neuro-
genesis and the high therapeutic efficacy of ECS therapy for
the treatment of mood disorders will be addressed in future
study.
Recent studies also addressed the mechanisms underlying
the neurogenic actions of antidepressants including ECS.12)
VEGF signaling is now considered as a main factor to medi-
ate increase of proliferation by ECS as well as other antide-
pressants27) (Fig. 2B). First, the time–course for induction of
VEGF by ECS in the dentate gyrus of the hippocampus is
consistent with that of neurogenesis. Second, VEGF infusion
into lateral ventricles is sufficient to increase both neural
stem and progenitor cells in SGZ of the dentate gyrus. More
importantly, blockade of VEGF signaling inhibits induction
of proliferation by ECS treatment. In contrast, BDNF is re-
quired for antidepressant regulation of survival of newborn
neurons, although not the proliferation.28)
As mentioned above, rapid progress has been made in un-
derstanding the mechanisms of gene regulation and neuroge-
nesis by ECS treatment in the hippocampus during the past
10 years. However, there are numerous unanswered questions
that need to be addressed about the molecular, cellular, and
behavioral effects of ECS. In the next section, I will focus on
the effect of ECS on mature neurons of the dentate gyrus in
the hippocampus.
3. MORPHOLOGICAL AND FUNCTIONAL CHANGES
IN MATURE NEURONS OF DENTATE GYRUS BY ECS
TREATMENT
Facilitated neurogenesis by ECS may alter functional roles
of the dentate gyrus in the hippocampal circuit. However,
since the number of additional new neurons would be only a
few percent of the total granule cells, the principal neurons
of the dentate gyrus, the modification of functions of existing
granule neurons by ECS treatment would also be important
for antidepressant actions. Neural stimulation by ECS in-
duces c-fos expression, a marker for neural activation, in
granule cells, as well as other gene induction such as BDNF
and COX-2 described in the previous section. This suggests
that ECS treatment activates mature granule cell neurons.
Then, what kind of morphological and functional changes
are induced by ECS in mature granule cells? To investigate
this, several studies were done in late 1990s.
Chronic ECS treatment induces sprouting of the granule
cell mossy fiber pathway, which provides the primary input
to CA3 pyramidal cells, in the hippocampus, whereas
chronic administration of chemical antidepressants such as
fluoxetine were ineffective.29,30) This indicates that induction
of mossy fiber sprouting by ECS is not a common property
of antidepressant therapies. It is possible that the ability to
induce sprouting might related to the superior efficacy of
ECS therapy when compared with chemical antidepressants
clinically. Alternatively, it may contribute to the transient
cognitive impairment that accompanies ECS in humans.31)
Electrophysiological changes in granule cell neurons by
ECS treatment were also examined.32,33) Chronic ECS treat-
ments enhance baseline levels of synaptic transmission in the
dentate gyrus. On the other hand, the level of experimentally
induced long-term potentiation (LTP) is reduced by ECS.
This reduction of LTP in ECS-treated animals could occur by
saturation of the potential to induce additional synaptic plas-
ticity in granule cells. These electrophysiological changes are
observed in fluoxetine-treated animals to a similar extent to
that in ECS-treated animals. These findings suggest that ECS
as well as chemical antidepressants induce LTP-like synaptic
changes, which may relate to stress-protective or cognitive
improvement mechanisms in granule cells of the dentate
gyrus.
Recently, interesting phenotypic changes of granule cell
neurons were reported in chemical antidepressant-treated
animals.34) Chronic fluoxetine treatment in mice strongly re-
duced expression of a mature granule cell marker, calbindin.
The fluoxetine-treated granule cells also exhibit immature-
like functional characteristics showing increased excitability
of granule cells and reduced mossy fiber synaptic facilita-
tion. These results suggest that chronic fluoxetine treatment
reverses the phenotypic maturation of adult dentate granule
cells especially in the functional aspect of maturation. Since
chronic fluoxetine treatments have also been shown to accel-
erate early maturational processes by inducing neurogene-
sis,35) this treatment seems to have bidirectional effects on
granular cell maturation, dependent on the maturational stage
of the cells. It is interesting whether ECS treatments or stress
stimuli also induce phenotypic changes of granular cells, and
if so, what signaling mediates to induce the changes. The
causal role of “dematurated” neurons in the behavioral ac-
tions of antidepressants will be also investigated.
4. POSSIBLE ROLES OF ECS-INDUCED COX-2 IN
HIPPOCAMPUS
COX enzyme catalyzes the first step in the synthesis of
prostanoids including prostaglandins and thromboxane and
exists in two isoforms, COX-1 and COX-2. Nonsteroidal
anti-inflammatory drugs such as indomethacin and aspirin
inhibit COX activity, leading to block prostanoid synthesis.
In the central nervous system, COX-2 is expressed constitu-
tively and also increased in neurons of the hippocampus by
various stimuli such as seizure and cerebral ischemia.36—38)
Both a single and chronic ECS treatments result in 20—
40-fold induction of COX-2 gene in the hippocampus espe-
cially in granule cells of the dentate gyrus9,36) (Fig. 1B).
July 2011 941
However, the role of ECS-induced COX-2 remains largely
unknown. In this section, I will summarize the role of COX-2
in the hippocampus and discuss possible effects of ECS-
induced COX-2 on memory retention, neuroprotection, and
neurogenesis.
Clinically, ECS therapy induces retrograde amnesia, which
refers to loss of previously acquired memories, and this is an
important reason that utilization of ECS therapy is low. Re-
cently, one group suggested involvement of COX-2 in ECS-
induced retrograde amnesia.39) Administration of five ECSs
resulted in significant retrograde amnesia on the step-down
passive avoidance task in rats. This memory impairment was
significantly protected by chronic treatment with celecoxib,
a COX-2 inhibitor, suggesting that COX-2-dependent
prostanoids are involved in ECS-induced memory impair-
ment. However, in physiological condition, several studies
showed that prostaglandins are involved in hippocampus-de-
pendent memory formation, and LTP formation at the per-
forant path-dentate gyrus synapse in the hippocampus.40,41)
Although the reason for the opposite effects of COX prod-
ucts on memory formation in different situations remains un-
known, it should be pointed out that the magnitude of ECS-
induced COX-2 upregulation is extremely high by hyper-
stimulation. It is possible that nonphysiological COX-2 in-
duction leads to neuronal excitotoxic changes contributing to
cognitive impairment. Thus it is interesting to examine how
ECS-evoked COX products of prostanoids affect electro-
physiological properties such as LTP formation in hippocam-
pal neurons so as to analyze the involvement of COX-2 in
ECS-induced memory impairment.
Chemically induced seizures such as kainic acid-induced
seizure also induce COX-2 gene expression in the hippocam-
pus.42) It is known that local or systemic administration of
kainic acid induces hippocampal neural loss. The effects of
COX inhibitors on kainic acid-induced neural cell death have
been examined. One study showed that pretreatment with the
COX-2 inhibitor NS-398 aggravates kainic-acid-induced
neural cell death and extends lesions to CA1 and CA3 re-
gions of the hippocampus,43) while another study indicated
that treatment with another COX-2 inhibitor, rofecoxib, after
kainic-acid injection reduces neural cell death in the CA1
and CA3 regions.44) These studies suggest that the time–
course and species of prostanoid production are important to
determine the neuroprotective or neurotoxic effects of
prostanoids. Since it has been reported that ECS-induced
seizure does not induce neural cell death in the hip-
pocampus,29) it is interesting whether ECS-induced pros-
tanoids by COX-2 activity have neuroprotective effects
against seizure.
It is also interesting whether COX-2 products are involved
in ECS-induced neurogenesis in the hippocampus. There are
several studies on the effects of prostanoids on neurogenesis
in the hippocampus. Direct infusion of a stable analog of
prostaglandin E2into the hippocampus increases cell prolif-
eration in the dentate gyrus of the hippocampus and these
cells express a neural marker suggesting prostaglandin E2has
stimulatory effects on the hippocampal neurogenesis.45)
Other reports examined the effect of COX-2 inhibitor on is-
chemia-induced neurogenesis in the dentate gyrus of the hip-
pocampus.46,47) Treatment with COX-2 inhibitor after is-
chemia inhibited enhancement of neural progenitor prolifera-
tion, indicating that COX-2 products play a role in the prolif-
eration of neural cells after ischemia. It will be examined
whether prostanoids are involved in ECS- or chemical anti-
depressant-induced neurogenesis.
Recently, research has focused on the roles of inflamma-
tory cytokines such as interleukin-1
b
(IL-1
b
) in stress re-
sponses and the etiology of depression.48) It is also well
known that prostaglandins, such as E2type, modulate pro-
duction of IL-1
b
in various types of cells including mi-
croglia.49) Future studies will pay attention to relations
among prostanoids, inflammatory cytokines, and mecha-
nisms of depression.
5. MOLECULAR AND CELLULAR CHANGES BY ECS
IN OTHER BRAIN REGIONS
ECS stimuli can induce molecular and cellular changes in
many brain regions other than hippocampus. For example,
ECS treatment increases cell proliferation in prefrontal cor-
tex, amygdala, and hypothalamus. In rat prefrontal cortex,
chronic ECS treatment increases the number of newly di-
vided cells and these cells express markers of either endothe-
lial cells or oligodendrocytes, but not neurons.50) In rat hypo-
thalamus, chronic ECS treatment induces an increase in en-
dothelial cell proliferation in specific areas such as paraven-
tricular nucleus and ventromedial hypothalamic nucleus.51) In
rat amygdala, chronic ECS stimulates cell proliferation in the
four main nuclei; a majority of the cells proliferating in re-
sponse to ECS are glial cells expressing the oligodendrocytes
progenitor marker.52) These results suggest that ECS treat-
ment activates many brain regions. Indeed, it has been re-
ported that a single ECS transiently increases c-fos expres-
sion in the hippocampus, prefrontal cortex, hypothalamus,
and amygdala, indicating that ECS induces neuronal activa-
tion in many areas (Fig. 1B).53) Upregulation of glia and en-
dothelial cells in response to ECS could serve to reverse the
atrophy and loss of cells that has been observed in depressed
patients.21) In addition, induction of endothelial cells by ECS
could indicate that there are changes in blood vessel structure
and integrity that could contribute to the actions of ECS. Ad-
ditional studies are needed to identify mediators responsible
for ECS-induced cell proliferation and to characterize their
function in models of depression.
ECS treatment also affects gene expression pattern in
many brain regions. Conti et al.54) examined transcriptional
changes induced by ECS as a fast-onset treatment in seven
different brain regions and compared them with those in-
duced by fluoxetine as a typical slow-onset SSRI treatment.
Two-day ECS treatment strongly affected the locus
coeruleus, indicating that fast-onset ECS action is associated
with “activation” of brain regions containing noradrenergic
neurons. On the other hand, the effects of 14-d SSRI treat-
ment were primarily in the dorsal raphe and hypothalamus.
As mentioned above, studies have shown that ECS induces
changes of gene expression pattern in many different brain
regions, but there are many questions that need to be ad-
dressed. For example, are there interactions in ECS-induced
transcriptional changes among different brain regions? Stud-
ies to identify the transcriptional changes in different regions
and to analyze these changes using bioinformatics approach
are needed. In addition, functional analysis is also important
942 Vol. 34, No. 7
to identify the roles of these gene products in antidepressant
actions. Region-specific approaches are needed further to an-
alyze the role of specific gene products in different regions.
6. BEHAVIORAL EFFECTS OF ECS TREATMENT IN
RODENT MODELS
The forced swim test is the most widely used animal
model in depression research. Although an acute treatment
with ECS did not reduce the duration of immobility in the
forced swim test of rats, chronic treatment with ECS signifi-
cantly reduced immobility time.55) In the tail suspension test
in mice, chronic ECS for 14 d showed a reduction of immo-
bility.56) Furthermore, ECS can abolish behavioral effects of
chronic stress on the forced swim test. One study showed that
daily restraint stress for 21 d displayed higher increases of
immobility in the forced swim test whereas ECS protected
against the deleterious effects of the stress paradigm.57) An-
other study showed that ECS treatment for 6 d decreased im-
mobility time in tricyclic antidepressant-resistant depressive
model of rats.58) This result suggests that ECS shows antide-
pressant-like action via different mechanisms from chemical
antidepressant pathway.
However, the behavioral analysis in the ECS model is in-
sufficient to understand clinical efficacy. Recently, several
behavioral paradigms that are dependent on long-term anti-
depressant administration were established. One example is
novelty-suppressed feeding; another is chronic unpredictable
stress-induced behavioral changes.12) Behavioral comparison
between ECS and chemical antidepressants on these para-
digms will help to identify similarities and differences of
these treatments. Especially, it is important to identify the
neural circuit and the molecular pathway to mediate the be-
havioral changes by ECS so as to find novel targets for anti-
depressants.
7. SUMMARY AND CONCLUSION
Here, I described the molecular, cellular, and behavioral
effects of ECS. In the dentate gyrus of the hippocampus,
ECS treatment regulates gene expression and increases neu-
rogenesis. Among genes regulated by ECS, neurotrophic/
growth factors and neuropeptides including BDNF, VEGF,
and VGF are especially noticeable, because they showed both
antidepressant-like and neurogenic effects. I also focused on
the role of COX-2 in the hippocampus, because induction of
this gene by ECS is very strong in the hippocampus. It has
been suggested that COX-2-derived products, prostanoids,
function in memory formation, neuroprotection, and neuro-
genesis in the hippocampus. The relation between the role of
COX-2 and antidepressant effects of ECS is an interesting
question. Chronic ECS treatment also induces morphological
and electrophysiological changes in mature granule neurons
of the dentate gyrus in the hippocampus, and increases glial
and endothelial proliferation in several brain regions includ-
ing prefrontal cortex, hypothalamus, and amygdala. The con-
tribution of these cellular changes to anti-stress and anti-
depressive effects will be addressed in future. At this point,
behavioral analysis in ECS treatment is insufficient to
understand clinical efficacy. It is important to identify the
neural circuit and the molecular pathway to mediate the be-
havioral changes by ECS. To identify the roles for molecular,
cellular, and behavioral effects on the action of ECS will pro-
vide new insights to find potential targets for novel anti-
depressant drug design.
Acknowledgement I am grateful to Drs. Atsushi
Ichikawa, Shuh Narumiya, Yukihiko Sugimoto, Ronald
Duman, and Yasushi Okuno for their encouragement and
criticism. I also thank Dr. Tomoyuki Furuyashiki, Ms. Mari
Sakaida, Mr. Yuhki Imoto, and Ms. Mamiko Sukeno for daily
discussions.
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