ArticlePDF AvailableLiterature Review

Exploration of New Molecular Mechanisms for Antidepressant Actions of Electroconvulsive Seizure


Abstract and Figures

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 therapeutic efficacy of ECS are not fully understood. Here, I review studies that show molecular, cellular, and behavioral changes by ECS treatment, and discuss the functions of ECS to underlie the action of antidepressant effects. In hippocampus, these changes cover gene induction, increased adult neurogenesis, and electrophysiological 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.
Content may be subject to copyright.
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.
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
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
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)
© 2011 Pharmaceutical Society of Japane-mail:
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
(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 (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
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.
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
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.
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
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
) 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
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.
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.
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-
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
1) Kessler R. C., McGonagle K. A., Zhao S., Nelson C. B., Hughes M.,
Eshleman S., Wittchen H. U., Kendler K. S., Arch. Gen. Psychiatry,
51, 8—19 (1994).
2) Nelson J. C., Biol. Psychiatry, 46, 1301—1308 (1999).
3) The U. K. ECT Review Group, Lancet, 361, 799—808 (2003).
4) Pagnin D., de Queiroz V., Pini S., Cassano G. B., J. ECT, 20, 13—20
5) Tanis K. Q., Duman R. S., Ann. Med., 39, 531—544 (2007).
6) Coyle J. T., Duman R. S., Neuron, 38, 157—160 (2003).
7) Duman R. S., Vaidya V. A., J. ECT, 14, 181—193 (1998).
8) Nibuya M., Morinobu S., Duman R. S., J. Neurosci., 15, 7539—7547
9) Newton S. S., Collier E. F., Hunsberger J., Adams D., Terwilliger R.,
Selvanayagam E., Duman R. S., J. Neurosci., 23, 10841—10851
10) Altar C. A., Laeng P., Jurata L. W., Brockman J. A., Lemire A.,
Bullard J., Bukhman Y. V., Young T. A., Charles V., Palfreyman M. G.,
J. Neurosci., 24, 2667—2677 (2004).
11) Warner-Schmidt J. L., Duman R. S., Proc. Natl. Acad. Sci. U.S.A., 104,
4647—4652 (2007).
12) Schmidt H. D., Duman R. S., Behav. Pharmacol., 18, 391—418
13) Shirayama Y., Chen A. C., Nakagawa S., Russell D. S., Duman R. S.,
J. Neurosci., 22, 3251—3261 (2002).
14) Redrobe J. P., Dumont Y., Fournier A., Quirion R., Neuropsychophar-
macology, 26, 615—624 (2002).
15) Ishida H., Shirayama Y., Iwata M., Katayama S., Yamamoto A., Kawa-
hara R., Nakagome K., Hippocampus, 17, 271—280 (2007).
16) Pekary A. E., Meyerhoff J. L., Sattin A., Brain Res., 884, 174—183
17) Levi A., Ferri G. L., Watson E., Possenti R., Salton S. R., Cell. Mol.
Neurobiol., 24, 517—533 (2004).
18) Levi A., Eldridge J. D., Paterson B. M., Science, 229, 393—395
19) Hunsberger J. G., Newton S. S., Bennett A. H., Duman C. H., Russell
D. S., Salton S. R., Duman R. S., Nat. Med., 13, 1476—1482 (2007).
20) Thakker-Varia S., Krol J. J., Nettleton J., Bilimoria P. M., Bangasser D.
A., Shors T. J., Black I. B., Alder J., J. Neurosci., 27, 12156—12167
21) Duman R. S., Biol. Psychiatry, 56, 140—145 (2004).
22) Warner-Schmidt J. L., Duman R. S., Hippocampus, 16, 239—249
23) Santarelli L., Saxe M., Gross C., Surget A., Battaglia F., Dulawa S.,
Weisstaub N., Lee J., Duman R., Arancio O., Belzung C., Hen R., Sci-
ence, 301, 805—809 (2003).
24) Malberg J. E., Eisch A. J., Nestler E. J., Duman R. S., J. Neurosci., 20,
9104—9110 (2000).
25) Segi-Nishida E., Warner-Schmidt J. L., Duman R. S., Proc. Natl.
Acad. Sci. U.S.A., 105, 11352—11357 (2008).
26) Encinas J. M., Vaahtokari A., Enikolopov G., Proc. Natl. Acad. Sci.
U.S.A., 103, 8233—8238 (2006).
27) Warner-Schmidt J. L., Duman R. S., Proc. Natl. Acad. Sci. U.S.A., 104,
4647—4652 (2007).
28) Sairanen M., Lucas G., Ernfors P., Castrén M., Castrén E., J.
Neurosci., 25, 1089—1094 (2005).
29) Vaidya V. A., Siuciak J. A., Du F., Duman R. S., Neuroscience, 89,
157—166 (1999).
July 2011 943
30) Lamont S. R., Paulls A., Stewart C. A., Brain Res., 893, 53—58
31) Weeks D., Freeman C. P., Kendell R. E., Br. J. Psychiatry, 137, 26—37
32) Stewart C., Jeffery K., Reid I., Neuroreport, 5, 1041—1044 (1994).
33) Stewart C. A., Reid I. C., Psychopharmacology, 148, 217—223
34) Kobayashi K., Ikeda Y., Sakai A., Yamasaki N., Haneda E., Miyakawa
T., Suzuki H., Proc. Natl. Acad. Sci. U.S.A., 107, 8434—8439 (2010).
35) Wang J. W., David D. J., Monckton J. E., Battaglia F., Hen R., J. Neu-
rosci., 28, 1374—1384 (2008).
36) Yamagata K., Andreasson K. I., Kaufmann W. E., Barnes C. A., Wor-
ley P. F., Neuron, 11, 371—386 (1993).
37) Kaufmann W. E., Worley P. F., Pegg J., Bremer M., Isakson P., Proc.
Natl. Acad. Sci. U.S.A., 93, 2317—2321 (1996).
38) Ohtsuki T., Kitagawa K., Yamagata K., Mandai K., Mabuchi T.,
Matsushita K., Yanagihara T., Matsumoto M., Brain Res., 736, 353—
356 (1996).
39) Andrade C., Singh N. M., Thyagarajan S., Nagaraja N., Sanjay Kumar
Rao N., Suresh Chandra J., J. Psychiatr. Res., 42, 837—850 (2008).
40) Rall J. M., Mach S. A., Dash P. K., Brain Res., 968, 273—276 (2003).
41) Yang H., Zhang J., Breyer R. M., Chen C., J. Neurochem., 108, 295—
304 (2009).
42) Chen J., Marsh T., Zhang J. S., Graham S. H., Neuroreport, 6, 245—
248 (1995).
43) Baik E. J., Kim E. J., Lee S. H., Moon C., Brain Res., 843, 118—129
44) Kunz T., Oliw E. H., Eur. J. Neurosci., 13, 569—575 (2001).
45) Uchida K., Kumihashi K., Kurosawa S., Kobayashi T., Itoi K.,
Machida T., Zoolog. Sci., 19, 1211—1216 (2002).
46) Sasaki T., Kitagawa K., Sugiura S., Omura-Matsuoka E., Tanaka S.,
Yagita Y., Okano H., Matsumoto M., Hori M., J. Neurosci. Res., 72,
461—471 (2003).
47) Kumihashi K., Uchida K., Miyazaki H., Kobayashi J., Tsushima T.,
Machida T., Neuroreport, 12, 915—917 (2001).
48) Koo J. W., Duman R. S., Curr. Opin. Investig. Drugs, 10, 664—671
49) Caggiano A. O., Kraig R. P., J. Neurochem., 72, 565—575 (1999).
50) Madsen T. M., Yeh D. D., Valentine G. W., Duman R. S., Neuropsy-
chopharmacology, 30, 27—34 (2005).
51) Jansson L., Hellsten J., Tingström A., Biol. Psychiatry, 60, 874—881
52) Wennström M., Hellsten J., Tingström A., Biol. Psychiatry, 55, 464—
471 (2004).
53) D’Costa A., Breese C. R., Boyd R. L., Booze R. M., Sonntag W. E.,
Brain Res., 567, 204—211 (1991).
54) Conti B., Maier R., Barr A. M., Morale M. C., Lu X., Sanna P. P.,
Bilbe G., Hoyer D., Bartfai T., Mol. Psychiatry, 12, 167—189 (2007).
55) Porsolt R. D., Anton G., Blavet N., Jalfre M., Eur. J. Pharmacol., 47,
379—391 (1978).
56) Christiansen S. H., Woldbye D. P., J. Neurosci. Res., 88, 3635—3643
57) Hageman I., Nielsen M., Wortwein G., Diemer N. H., Jorgensen M. B.,
Behav. Brain Res., 196, 71—77 (2009).
58) Li B., Suemaru K., Cui R., Kitamura Y., Gomita Y., Araki H., Eur. J.
Pharmacol., 529, 114—121 (2006).
944 Vol. 34, No. 7
... At the indicated times (see Figs. 1 -5 ), rats were killed by rapid decapitation, the left half-brain was quickly isolated, frozen in −30 °C isopentane and stored at −80 °C until 30 μm serial sections were cryostat-cut throughout the whole extent of the hippocampus ( −1.72 to −6.80 mm from Bregma) and slide-mounted (e.g., 8 tissue-sections per slide, 8 slides per series, 3 series per animal: series 1 being the most anterior part of the hippocampus, series 2 the middle part and series 3 the most posterior part of it) as previously performed ( García-Fuster et al., 2010, 2011. The rate of cell genesis was evaluated for all experimental samples by immunohistochemical analysis with the following markers: Ki-67 for recent cell proliferation and NeuroD for early neuronal survival ( García-Fuster et al., 2010, 2011 in the dentate gyrus. ...
... At the indicated times (see Figs. 1 -5 ), rats were killed by rapid decapitation, the left half-brain was quickly isolated, frozen in −30 °C isopentane and stored at −80 °C until 30 μm serial sections were cryostat-cut throughout the whole extent of the hippocampus ( −1.72 to −6.80 mm from Bregma) and slide-mounted (e.g., 8 tissue-sections per slide, 8 slides per series, 3 series per animal: series 1 being the most anterior part of the hippocampus, series 2 the middle part and series 3 the most posterior part of it) as previously performed ( García-Fuster et al., 2010, 2011. The rate of cell genesis was evaluated for all experimental samples by immunohistochemical analysis with the following markers: Ki-67 for recent cell proliferation and NeuroD for early neuronal survival ( García-Fuster et al., 2010, 2011 in the dentate gyrus. Briefly, as priory detailed ( García-Fuster et al., 2010, 2011, 3 slides (1 from each series, 24 tissue-sections in total) per animal and marker were postfixed (4% paraformaldehyde) and exposed to several steps (e.g., antigen retrieval, blocking in peroxidase solution and BSA) before overnight incubation with polyclonal rabbit anti-Ki-67 (1:40,000; kindly provided by Drs. ...
... The rate of cell genesis was evaluated for all experimental samples by immunohistochemical analysis with the following markers: Ki-67 for recent cell proliferation and NeuroD for early neuronal survival ( García-Fuster et al., 2010, 2011 in the dentate gyrus. Briefly, as priory detailed ( García-Fuster et al., 2010, 2011, 3 slides (1 from each series, 24 tissue-sections in total) per animal and marker were postfixed (4% paraformaldehyde) and exposed to several steps (e.g., antigen retrieval, blocking in peroxidase solution and BSA) before overnight incubation with polyclonal rabbit anti-Ki-67 (1:40,000; kindly provided by Drs. Huda Akil and Stanley J. Watson, University of Michigan, MI, USA) or goat anti-NeuroD (1:25,000; Santa Cruz Biotechnology, CA, USA). ...
Full-text available
Age and sex are critical factors for the diagnosis and treatment of major depression, since there is a well-known age-by-sex difference in the prevalence of major depression (being females the most vulnerable ones) and in antidepressant efficacy (being adolescence a less responsive period than adulthood). Although the induction of electroconvulsive seizures (ECS) is a very old technique in humans, there is not much evidence reporting sex- and age-specific aspects of this treatment. The present study evaluated the antidepressant- and neurogenic-like potential of repeated ECS across time in adolescent and adult rats (naïve or in a model of early life stress capable of mimicking a pro-depressive phenotype), while including a sex perspective. The main results demonstrated age- and sex-specific differences in the antidepressant-like potential of repeated ECS, since it worked when administered during adolescence or adulthood in male rats (although with a shorter length in adolescence), while in females rendered deleterious during adolescence and ineffective in adulthood. Yet, repeated ECS increased cell proliferation and vastly boosted young neuronal survival in a time-dependent manner for both sexes and independently of age. Moreover, pharmacological inhibition of basal cell proliferation prevented the antidepressant-like effect induced by repeated ECS in male rats, but only partially blocked the very robust increase in the initial cell markers of hippocampal neurogenesis. Overall, the present results suggest that the induction of the early phases of neurogenesis by ECS, besides having a role in mediating its antidepressant-like effect, might participate in some other neuroplastic actions, opening the path for future studies.
... Many previous studies found micro and macroscopic changes in the hippocampus during electrical stimulation of the brain [14,[25][26][27][28][29][30], but the specificity and functional relevance of these findings has remained controversial [14,20,[27][28][29][30]. Our results validate the central role of the hippocampus in the cognitive side effects of ECT. ...
... Based on these results, we can only speculate about the biological underpinnings responsible for the hippocampal volume change. As discussed in detail in our previous report [27], ECT-induced volume changes can be due to fluid shifts due to vascularization [50], blood flow change [51,52], inflammation [53][54][55][56] or vasogenic oedema [57][58][59] and/or neuroplastic mechanisms including neurogenesis [26,[60][61][62], synaptogenesis [63,64] and gliogenesis [65]. Some of these mechanisms are more likely than others given the widespread changes related to and the timescale of the intervention, but more preclinical studies will be required to shed light on the exact nature of these volume changes. ...
Full-text available
Abstract Electroconvulsive therapy (ECT) is of the most effective treatments available for treatment-resistant depression, yet it is underutilized in part due to its reputation of causing cognitive side effects in a significant number of patients. Despite intensive neuroimaging research on ECT in the past two decades, the underlying neurobiological correlates of cognitive side effects remain elusive. Because the primary ECT-related cognitive deficit is memory impairment, it has been suggested that the hippocampus may play a crucial role. In the current study, we investigated 29 subjects with longitudinal MRI and detailed neuropsychological testing in two independent cohorts (N = 15/14) to test if volume changes were associated with cognitive side effects. The two cohorts underwent somewhat different ECT study protocols reflected in electrode placements and the number of treatments. We used longitudinal freesurfer algorithms (6.0) to obtain a bias-free estimate of volume changes in the hippocampus and tested its relationship with neurocognitive score changes. As an exploratory analysis and to evaluate how specific the effects were to the hippocampus, we also calculated this relationship in 41 other areas. In addition, we also analyzed cognitive data from a group of healthy volunteers (N = 29) to assess practice effects. Our results supported the hypothesis that hippocampus enlargement was associated with worse cognitive outcomes, and this result was generalizable across two independent cohorts with different diagnoses, different electrode placements, and a different number of ECT sessions. We found, in both cohorts, that treatment robustly increased the volume size of the hippocampus (Cohort 1: t = 5.07, Cohort 2: t = 4.82; p
... The findings of several animal trials support a role for VEGF in the biological actions of antidepressants (i.e., fluoxetine) (46) and mood stabilizers (i.e., lamotrigine) (47). Similarly, VEGF could mediate the antidepressant actions of electroconvulsive seizures (48,49) and a single ketamine infusion (28) but not six ketamine infusions (29). However, in this study, we found that VEGF was not involved in the antisuicidal effects of repeated-dose intravenous ketamine in Chinese patients with depression and suicidal ideation, which should be confirmed by RCTs. ...
Full-text available
Objectives Accumulating evidence supports a role for vascular endothelial growth factor (VEGF) in the pathogenesis of depression, but its relationship with the antisuicidal effects of ketamine is not clear. Our objective was to determine whether there was an association between the plasma VEGF (pVEGF) concentrations and the antisuicidal response to serial ketamine infusions. Methods Six ketamine infusions (0.5 mg/kg) over a 12-day period were administered to sixty depressed individuals suffering from suicidal ideation. The Hamilton Depression Rating Scale (HAMD) suicide item, the Montgomery-Åsberg Depression Rating Scale (MADRS) suicide item, and the Beck Scale for Suicide Ideation (SSI-part I) were used to assess suicidal ideation at baseline, 1 day after the first infusion (day 1), 1 day following the last infusion (day 13), and again 2 weeks post-infusion (day 26). For this purpose, plasma was obtained at baseline, day 13 and 26. Results The rates of antisuicidal response to ketamine were 61.7% (37/60), 81.7% (49/60), and 73.3% (44/60) at days 1, 13, and 26, respectively. The linear mixed model revealed significant time effects on suicidal ideation and pVEGF concentrations over time (all Ps < 0.05). Antisuicidal responders did not have significantly altered pVEGF concentrations compared with non-responders on day 13 and day 26 (all Ps > 0.05). No significant correlation was found between the baseline pVEGF concentration and suicidal ideation as measured by the SSI part 1, HAMD suicide item and MADRS suicide item on days 1, 13, and 26 (all ps > 0.05). Conclusion This preliminary finding does not support a role for VEGF in the antisuicidal effects of serial ketamine treatments in individuals with depression and suicidal ideation. Further research is needed to confirm and expand these findings.
... Several limitations should be considered when interpreting these results. First, seizure is an important therapeutic component of ECT [56], but the impact of seizure on neuroplasticity and clinical outcomes was not assessed with this investigation. Seizure activity may be related to neuroplasticity with and without E-field generation (i.e., Metrazol therapy) [57,58]. ...
Full-text available
Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes, but the underlying mechanisms for antidepressant response and procedure-induced cognitive side effects have yet to be elucidated. Such mechanisms may be complex and involve certain ECT parameters and brain regions. Regarding parameters, the electrode placement (right unilateral or bitemporal) determines the geometric shape of the electric field (E-field), and amplitude determines the E-field magnitude in select brain regions (e.g., hippocampus). Here, we aim to determine the relationships between hippocampal E-field strength, hippocampal neuroplasticity, and antidepressant and cognitive outcomes. We used hippocampal E-fields and volumes generated from a randomized clinical trial that compared right unilateral electrode placement with different pulse amplitudes (600, 700, and 800 mA). Hippocampal E-field strength was variable but increased with each amplitude arm. We demonstrated a linear relationship between right hippocampal E-field and right hippocampal neuroplasticity. Right hippocampal neuroplasticity mediated right hippocampal E-field and antidepressant outcomes. In contrast, right hippocampal E-field was directly related to cognitive outcomes as measured by phonemic fluency. We used receiver operating characteristic curves to determine that the maximal right hippocampal E-field associated with cognitive safety was 112.5 V/m. Right hippocampal E-field strength was related to the whole-brain ratio of E-field strength per unit of stimulation current, but this whole-brain ratio was unrelated to antidepressant or cognitive outcomes. We discuss the implications of optimal hippocampal E-field dosing to maximize antidepressant outcomes and cognitive safety with individualized amplitudes.
... A variety of studies have shown that ECT alters cerebral blood flow and glucose metabolism, using neuroimaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI) (28). ECT also modulates the neurotransmission process and influences the expression as well as the release of a wide variety of neurotransmitters in the brain, including transcription factors, neurotransmitters, neurotrophic factors and hormones (29). It has an effect on the transmission of almost all major neurotransmitters in the brain, such as: serotonin, dopamine, acetylcholine, endogenous opioids, epinephrine and norepinephrine (30). ...
Full-text available
Electroconvulsive therapy (ECT) is a technique that has been used since 1938 to treat several psychiatric disorders as a replacement for chemically induced seizures. Despite its history of stigma, controversy and low accessibility, ECT is found to be beneficial and efficient in severe cases of depression where medication fails to bring results. Titration tables developed over time, based on evidenced-based medicine, have made this treatment technique safe and, in some cases, the first choice of treatment. The aim of the review was to summarize the research conducted on the efficacy of ECT on major depressive disorder and variables studied such as technique, comorbidities and medication as well as the effects and outcomes of this procedure. At the same time, the application and correlations with other psychiatric and neurological disorders, including catatonia, agitation and aggression in individuals with dementia, schizophrenia, and epilepsy were assessed. There are no statistically demonstrated effects due to the fact that a small number of moderate-quality studies have been published; however, the combination of ECT technique with standard medication and care, can improve patient outcome. Furthermore, with regard to ECT, widespread and robust volume changes in both cortical and subcortical regions have been shown. Antidepressant response and volumetric increases appear to be limited by the specific neuroplasticity threshold of each patient.
... Presently, the mechanism(s) by which MST elicits its antidepressant effects remain uncertain. Convulsive therapies can produce global changes in network dynamics, which likely result from complex and widespread neurochemical and metabolic alterations throughout the brain (Atluri et al., 2018;Sackeim, 2004;Singh and Kar, 2017;Segi-Nishida, 2011). Results from functional neuroimaging studies indicate a degree of hypo-connectivity within fronto-parietal regions linked to executive function and cognitive control in MDD (Kaiser et al., 2015). ...
Magnetic seizure therapy (MST) is emerging as a safe and well-tolerated experimental intervention for major depressive disorder (MDD), with very minimal cognitive side-effects. However, the underlying mechanism of action of MST remains uncertain. Here, we used resting-state electroencephalography (RS-EEG) to characterise the physiological effects of MST for treatment resistant MDD. We recorded RS-EEG in 21 patients before and after an open label trial of MST applied over the prefrontal cortex using a bilateral twin coil. RS-EEG was analysed for changes in functional connectivity, network topology, and spectral power. We also ran further baseline comparisons between the MDD patients and a cohort of healthy controls (n = 22). Network-based connectivity analysis revealed a functional subnetwork of significantly increased theta connectivity spanning frontal and parieto-occipital channels following MST. The change in theta connectivity was further found to predict clinical response to treatment. An additional widespread subnetwork of reduced beta connectivity was also elucidated. Graph-based topological analyses showed an increase in functional network segregation and reduction in integration in the theta band, with a decline in segregation in the beta band. Finally, delta and theta power were significantly elevated following treatment, while gamma power declined. No baseline differences between MDD patients and healthy subjects were observed. These results highlight widespread changes in resting-state brain dynamics following a course of MST in MDD patients, with changes in theta connectivity providing a potential physiological marker of treatment response. Future prospective studies are required to confirm these initial findings.
... Several neuroplastic mechanisms including neurogenesis, angiogenesis, synaptogenesis, gliogenesis may be specific to the rapidly changing electric field (Bouckaert et al., 2014;Tang et al., 2017). Although heavily debated (Sorrells et al., 2018;Boldrini et al., 2018;Andreae, 2018), the support for adult neurogenesis is based on pre-clinical studies demonstrating neuronal division and differentiation related to suprathreshold electric stimulation (Scott et al., 2000;Madsen et al., 2000;Perera et al., 2007;Segi-Nishida, 2011). However, neurogenesis as the sole mechanism of neuroplasticity may be incompatible with the time frame and expansive volume change. ...
... The therapeutic effect of ECT is dependent on the induction of generalized seizures, and repeated treatments are required to induce the therapeutic actions of ECT (Lisanby, 2007;Weiner and Reti, 2017). Repeated electroconvulsive seizure (ECS) treatment, an animal model of ECT, induces cellular proliferation, synaptic modifications, increased expression of neurotrophic factors, and changes in the activity of intracellular signaling molecules (Segi-Nishida, 2011), resulting in the long-term plastic changes induced by ECS. However, the mechanism of action whereby ECT-induced generalized seizures alter brain physiology and relieve the symptoms of psychiatric and neurological disorders needs further clarification. ...
Full-text available
Background: It is uncertain how electroconvulsive therapy (ECT)-induced generalized seizures exert their potent therapeutic effects on various neuropsychiatric disorders. Adenosine monophosphate-activated protein kinase (AMPK) plays a major role in maintaining metabolic homeostasis, and activates autophagic processes via unc-51-like kinase (ULK1). Evidence supports the involvement of autophagy system in the action mechanisms of antidepressants and antipsychotics. The effect of ECT on autophagy-related signaling requires further clarification. Methods: The effect of electroconvulsive seizure (ECS) on autophagy, and its association with the AMPK signaling pathway, were investigated in the rat frontal cortex. ECS was provided once per day for 10 days (E10X), and compound C or 3-methyadenine was administered through an intracerebroventricular (i.c.v.) cannula. Molecular changes were analyzed with immunoblot, immunohistochemistry, and transmission electron microscopy (TEM) analyses. Results: E10X increased p-Thr172-AMPKα immunoreactivity in rat frontal cortex neurons. E10X increased phosphorylation of upstream effectors of AMPK, such as LKB1, CaMKK, and TAK1, and of its substrates, ACC, HMGR, and GABABR2. E10X also increased p-Ser317-ULK1 immunoreactivity. At the same time, LC3-II and ATG5-ATG12 conjugate immunoreactivity increased, indicating activation of autophagy. An i.c.v injection of the AMPK inhibitor compound C attenuated the ECS-induced increase in ULK1 phosphorylation, as well as the protein levels of LC3-II and Atg5-Atg12 conjugate. TEM clearly showed an increased number of autophagosomes in the rat frontal cortex after E10X, which was reduced by i.c.v treatment with the autophagy inhibitor 3-methyadenine and compound C. Conclusions: Repeated ECS treatments activated in vivo autophagy in the rat frontal cortex through the AMPK signaling pathway.
Full-text available
Recent longitudinal neuroimaging studies in patients with electroconvulsive therapy (ECT) suggest local effects of electric stimulation (lateralized) occur in tandem with global seizure activity (generalized). We used electric field (EF) modeling in 151 ECT treated patients with depression to determine the regional relationships between EF, unbiased longitudinal volume change, and antidepressant response across 85 brain regions. The majority of regional volumes increased significantly, and volumetric changes correlated with regional electric field (t =3.77, df = 83, r = 0.38, p = 0.0003). After controlling for nuisance variables (age, treatment number, and study site), we identified two regions (left amygdala and left hippocampus) with a strong relationship between EF and volume change (FDR corrected p<0.01). However, neither structural volume changes nor electric field was associated with antidepressant response. In summary, we showed that high electrical fields are strongly associated with robust volume changes in a dose-dependent fashion.
Approximately one third of patients with depression remain treatment resistant with existing antidepressants, suggesting that the currently-available antidepressants cannot induce appropriate responses in the brains of all patients. Long-term exposure to adrenocorticotrophic hormone (ACTH) has been proposed as a model that mimics at least some aspects of clinical treatment-resistant depression in rodents. The purpose of this study was to explore potential causes of antidepressant treatment resistance using the chronic ACTH-treated mouse model. We subjected ACTH-treated mice to a rodent model of electroconvulsive therapy, i.e., electroconvulsive seizure (ECS), which induces various molecular and cellular changes, including in gene expression and adult neurogenesis in the hippocampus. First, behavioral effect of repeated ECS in the forced swim test (FST) was examined. In our experimental setting, ACTH-treated mice showed resistance to the antidepressant-like effect of ECS in the FST. We then examined which cellular and molecular changes induced by ECS were attenuated by ACTH administration. Chronic ACTH treatment suppressed the increase of gene expression such as of Bdnf, Npy, and Drd1 induced by ECS in the hippocampus. In contrast, there was no difference in ECS-induced promotion of the early neurogenetic process in the hippocampus between ACTH-treated and control mice. Our results suggest the possibility that impaired neuromodulation and monoamine signaling in the hippocampus are among the factors contributing to antidepressant treatment resistance.
Full-text available
Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells. Chronic treatments of adult mice with fluoxetine strongly reduced expression of the mature granule cell marker calbindin. The fluoxetine treatment induced active somatic membrane properties resembling immature granule cells and markedly reduced synaptic facilitation that characterizes the mature dentate-to-CA3 signal transmission. These changes cannot be explained simply by an increase in newly generated immature neurons, but best characterized as "dematuration" of mature granule cells. This granule cell dematuration developed along with increases in the efficacy of serotonin in 5-HT(4) receptor-dependent neuromodulation and was attenuated in mice lacking the 5-HT(4) receptor. Our results suggest that serotonergic antidepressants can reverse the established state of neuronal maturation in the adult hippocampus, and up-regulation of 5-HT(4) receptor-mediated signaling may play a critical role in this distinct action of antidepressants. Such reversal of neuronal maturation could affect proper functioning of the mature hippocampal circuit, but may also cause some beneficial effects by reinstating neuronal functions that are lost during development.
Full-text available
All classes of antidepressants increase hippocampal cell proliferation and neurogenesis, which contributes, in part, to the behavioral actions of these treatments. Among antidepressant treatments, electroconvulsive seizure (ECS) is the most robust stimulator of hippocampal cell proliferation and the most efficacious treatment for depression, but the cellular mechanisms underlying the actions of ECS are unknown. To address this question, we investigated the effect of ECS on proliferation of neural stem-like and/or progenitor cells in the subgranular zone of rat dentate gyrus. We define the neural differentiation cascade from stem-like cells to early neural progenitors (also referred to as quiescent and amplifying neural progenitors, respectively) by coexpression of selective cellular and mitotic activity markers. We find that at an early mitotic phase ECS increases the proliferation of quiescent progenitors and then at a later phase increases the proliferation of amplifying progenitors. We further demonstrate that vascular endothelial growth factor (VEGF) signaling is necessary for ECS induction of quiescent neural progenitor cell proliferation and is sufficient to produce this effect. These findings demonstrate that ECS and subsequent induction of VEGF stimulates the proliferation of neural stem-like cells and neural progenitor cells, thereby accounting for the superior neurogenic actions of ECS compared with chemical antidepressants.
Reviewed published work for the efficacy and safety of electroconvulsive therapy (ECT) vs simulated ECT, ECT vs pharmacotherapy, and different forms of ECT for patients with depressive illness. The authors designed a systematic overview and meta-analysis of randomised controlled trials and observational studies. They obtained data from the Cochrane Collaboration Depressive Anxiety and Neurosis and Schizophrenia Group Controlled trial registers, Cochrane Controlled Trials register, Biological Abstracts, CINAHL, EMBASE, LILACS, MEDLINE, PsycINFO, and SIGLE, reference lists, and specialist textbooks. The main outcome measures were depressive symptoms, measures of cognitive function, and mortality. Meta-analysis of data of short-term efficacy from randomised controlled trials was possible. Real ECT was significantly more effective than simulated ECT (6 trials, 256 Ss). Treatment with ECT was significantly more effective than pharmacotherapy (18 trials, 1144 Ss). Bilateral ECT was more effective than unipolar ECT (22 trials, 1408 Ss). It is concluded that ECT is an effective short-term treatment for depression, and is probably more effective than drug therapy. Bilateral ECT is moderately more effective than unilateral ECT, and high dose ECT is more effective than low dose. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Animal models of chronic stress, such as 21 days of 6 h/daily restraint stress cause changes in neuronal morphology in the hippocampus and alter behaviour. These changes are partly mediated by the glucocorticoids.The objective of this study was threefold: (1) to study how this particular chronic stress paradigm influences expression of hippocampal glucocorticoid receptor mRNA, (2) to study the effect of previous repeated restraint stress on the behaviours executed in the forced swim test (FST) (e.g. a novel inescapable stress situation) and (3) to investigate the modulating effect of electroconvulsive stimulations (ECS) on the neural and behavioural effects of the stress paradigm.The study shows that restraint stress lowered glucocorticoid receptor mRNA levels in all hippocampal regions, including the CA3 region which is the site of the characteristic dendritic reorganization seen in this model. Furthermore, stressed rats displayed higher increases in immobility and decreased latency to immobility subjected to the novel stressor of the FST than non-stressed rats. ECS abolished both the neural and behavioural effects of the restraint stress and thus protected against the deleterious effects of the stress paradigm. The clinical relevance of these findings is discussed.
Even though induction of seizures by electroconvulsive stimulation (ECS) is a treatment widely used for major depression in humans, the working mechanism of ECS remains uncertain. The antiepileptic effect of ECS has been suggested to be involved in mediating the therapeutic effect of ECS. The neuropeptide galanin exerts antiepileptic and antidepressant-like effects and has also been implicated in the pathophysiology of depression. To explore a potential role of galanin in working mechanisms of ECS, the present study examined effects of repeated ECS on the galanin system using QRT-PCR, in situ hybridization, and [(125) I]galanin receptor binding. ECS was administered to adult mice daily for 14 days, and this paradigm was confirmed to exert antidepressant-like effect in the tail suspension test. Prominent increases in galanin gene expression were found in several brain regions involved in regulation of epileptic activity and depression, including the piriform cortex, hippocampal dentate gyrus, and amygdala. Likewise, GalR2 gene expression was up-regulated in both the central and the medial amygdala, whereas GalR1 gene expression showed a modest down-regulation in the medial amygdala. [(125) I]galanin receptor binding in the piriform cortex, hippocampus, and amygdala was found to be significantly down-regulated. These data show that the galanin system is regulated by repeated ECS in a number of brain regions implicated in seizure regulation and depression. These changes may play a role in the therapeutic effect of ECS.
Uncontrollable stress, a major precipitant of depression in humans and in animal paradigms, impairs hippocampal neurogenesis, which is necessary for the behavioral effects of antidepressants in models of depression that require chronic treatment. However, the mechanisms underlying these anti-neurogenic and behavioral effects of stress have not been elucidated. Proinflammatory cytokines are thought to be contributing factors to stress and have been implicated in stress-related mood disorders such as major depression. In particular, IL-1 beta has been proposed to be a key mediator in a variety of behavioral actions of stress. Notably, the administration of a IL-1 receptor antagonist (IL-1Ra) blocks the stress-like effects of IL-1 beta in both cellular and behavioral models. This review highlights the increasing interest in the relationship between IL-1 beta, neurogenesis, stress and depression, and discusses the potential of IL-1Ra or other cytokine antagonists as new candidates for the treatment of depression.
Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a pre-synaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were normal. Importantly, escape latency in the water maze in EP2 KO was longer than that in age-matched EP2 wild-type littermates (WT). We also observed that long-term potentiation was potentiated in EP2 WT animals that received lipopolysaccharide (LPS, i.p.), but not in EP2 KO. Bath application of PGE2 or butaprost, an EP2 receptor agonist, increased synaptic transmission and decreased paired-pulses ratio in EP2 WT mice, but failed to induce the changes in EP2 KO mice. Meanwhile, synaptic transmission was elevated by application of forskolin, an adenylyl cyclase activator, both in EP2 KO and WT animals. In addition, the PGE2-enhanced synaptic transmission was significantly attenuated by application of PKA, IP3 or MAPK inhibitors in EP2 WT animals. Our results show that hippocampal long-term synaptic plasticity is impaired in mice deficient in the EP2, suggesting that PGE2-EP2 signaling is important for hippocampal long-term synaptic plasticity and cognitive function.
Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.
c-fos is a proto-oncogene that encodes for a nuclear phosphoprotein with DNA binding properties and is presumed to have an important role in the long-term regulation of neuronal function. It is thought to act as a 'third messenger' molecule in signal transduction systems and its expression has been shown to be induced by a variety of exogenous and endogenous stimuli. This study examines the differential expression of the Fos protein in various brain regions after a single electroconvulsive shock (ECS) in 6-, 13-, and 28-month-old B6C3 mice. The animals received an acute electroconvulsive shock (90 V for 0.3 s), without prior anesthesia, through earclip electrodes and exhibited generalized tonic-clonic seizures lasting 20-36 s. Animals were anesthetized and perfused intracardially with 2.5% acrolein, 4% paraformaldehyde at 0.5, 1.0, 2.0 and 4.0 h postshock. The brains were Vibratome-sectioned (30 microns) and examined using a Fos antibody, directed against a conserved region of both mouse and human Fos by standard immunocytochemical methods. Systematic sampling of the total number of Fos immunostained neurons in amygdala, hippocampus and the cerebral cortex showed peak values at the 1-h time point followed by a steady decline thereafter in all age groups. In a second experiment, Fos-like immunoreactivity was compared 1 h after ECS in the hippocampus, amygdala and the cortex in all 3 age groups. There was increased expression of Fos-like immunoreactivity after ECS- compared to non-ECS-treated controls in all age groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Nerve growth factor (NGF) is essential for the development and differentiation of sympathetic or sensory neurons. A complementary DNA was cloned that corresponds to a gene sequence induced more than 50-fold in a cultured target cell line of pheochromocytoma cells (PC12 cells) 5 hours after the addition of NGF. The induced messenger RNA encodes a 90,000-dalton polypeptide that may represent one of the primary events in NGF-induced differentiation of neurons.