Electroconvulsive shock ameliorates disease
processes and extends survival in huntingtin
Mohamed R. Mughal1, Akanksha Baharani2, Srinivasulu Chigurupati1,2, Tae Gen Son1,
Edmund Chen1, Peter Yang1, Eitan Okun1, Thiruma Arumugam3, Sic L. Chan2,∗
and Mark P. Mattson1,4,∗
1Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Biomedical Research
Center, Baltimore, MD 21224, USA,2Burnett School of Biomedical Sciences, College of Medicine, University of
Central Florida, Orlando, FL 32816, USA,3School of Biomedical Sciences, University of Queensland, Brisbane,
Australia and4Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Received October 12, 2010; Revised October 12, 2010; Accepted November 19, 2010
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by expanded polyglutamine
repeats in the huntingtin (Htt) protein. Mutant Htt may damage and kill striatal neurons by a mechanism invol-
ving reduced production of brain-derived neurotrophic factor (BDNF) and increased oxidative and metabolic
stress. Because electroconvulsive shock (ECS) can stimulate the production of BDNF and protect neurons
against stress, we determined whether ECS treatment would modify the disease process and provide a thera-
peutic benefit in a mouse model of HD. ECS (50 mA for 0.2 s) or sham treatment was administered once
weekly to male N171-82Q Htt mutant mice beginning at 2 months of age. Endpoints measured included
motor function, striatal and cortical pathology, and levels of protein chaperones and BDNF. ECS treatment
delayed the onset of motor symptoms and body weight loss and extended the survival of HD mice. Striatal
neurodegeneration was attenuated and levels of protein chaperones (Hsp70 and Hsp40) and BDNF were elev-
ated in striatal neurons of ECS-treated compared with sham-treated HD mice. Our findings demonstrate that
ECS can increase the resistance of neurons to mutant Htt resulting in improved functional outcome and
extended survival. The potential of ECS as an intervention in subjects that inherit the mutant Htt gene
merits further consideration.
Huntington’s disease (HD) is an inherited neurological dis-
order that includes prominent motor, psychiatric and cognitive
symptoms resulting from degeneration of neurons in the stria-
tum and cerebral cortex (1). The genetic defect is the presence
of expanded CAG repeats in the huntingtin gene resulting in
long (.36) repeats of the amino acid glutamine in the hunting-
tin protein (Htt) (2,3). The function of normal Htt in neurons is
unknown, although it may play roles in axonal and vesicle traf-
ficking (4) and regulation of synaptic activity (5). Htt is widely
expressed in neurons throughout the brain, and it remains
unclear why striatal medium spiny neurons are particularly
vulnerable to mutant Htt. The precise molecular mechanisms
by which mutant Htt exerts its toxicity remain unknown,
although several pathogenic mechanisms have been proposed
including adverse actions on the mitochondrial function and
neurotrophic signaling (6). In vulnerable neurons, mutant Htt
forms intranuclear inclusions, and a similar protein aggrega-
tion process occurs when mutant Htt is expressed in cultured
cells and transgenic mice (7,8).
One alteration that is implicated in the demise of striatal and
cortical neurons in HD is a deficit in brain-derived neuro-
trophic factor (BDNF). Analyses of postmortem brain tissue
samples from HD patients (9) and from multiple lines of Htt
mutant mice (10,11) have demonstrated reduced levels of
∗To whom correspondence should be addressed at: Burnett School of Biomedical Sciences College of Medicine, University of Central Florida, 4000
Central Florida Blvd., Orlando, FL 32816, USA. Tel: +1 4078233585; Fax: +1 4078230956; Email: firstname.lastname@example.org (S.L.C.); Tel: +1
4105588463; Fax: +1 4105588465; Email: email@example.com (M.P.M.)
Published by Oxford University Press 2010.
Human Molecular Genetics, 2011, Vol. 20, No. 4
Advance Access published on November 24, 2010
BDNF in the striatum and cerebral cortex. The reduction in
BDNF levels may contribute to the degeneration of striatal
and cortical neurons because BDNF can protect these neuronal
populations against insults relevant to HD in cell culture and
animal models (12–14). In addition, elevation of BDNF
levels by overexpression of the BDNF gene in the striatum
and cortex counteracts the neurodegenerative effects of
mutant Htt and extends survival in mouse models of HD
(11,15). Moreover, BDNF haploinsufficiency accelerates the
neurodegenerative process in Htt mutant mice with the enke-
phalinergic striatal projection neurons being the most vulner-
able to reduced BDNF levels (16). Mutant Htt impairs
transcription of the BDNF gene by altering the interactions
of the transcriptional regulators REST and cAMP response
element-binding protein (CREB) with their DNA regulatory
elements (17,18). Consistent with a role for reduced BDNF
signaling in HD pathogenesis, dietary energy restriction (10)
and environmental enrichment (19) increase BDNF levels in
striatum and cortex and retard neurodegeneration in HD
Electroconvulsive shock (ECS) is a clinical procedure that
improves symptoms in many patients with severe depression
(20). ECS treatment has also been reported to be effective in
reducing psychiatric symptoms in patients with Alzheimer’s
(21) and Parkinson’s (22) diseases. There have been a few
case reports describing beneficial effects of ECS treatment
on depressive symptoms in HD patients (23) and at least one
report of improvement in motor symptoms in an HD patient
(24). ECS might be expected to counteract the pathogenic
actions of mutant Htt, because ECS is potent inducer of
BDNF production (25,26). Here we report that ECS treatment
suppresses the neurodegenerative process and extends the sur-
vival of Htt mutant mice by a mechanism involving
up-regulation of the expression of protein chaperones and
ECS ameliorates motor deficits and improves survival
in N171-82Q HD mice
Previous studies showed that N171-82Q HD mice have an
abbreviated lifespan of about 21–22 weeks; they exhibit
motor deficits beginning at 14–16 weeks of age (27). To deter-
mine whether ECS provides significant clinical benefits in an
animal model, we assessed the impact of ECS on the develop-
ment of behavioral symptoms and the survival of male
N171-82Q HD mice. Beginning at 2 months of age, 20 wild-
type (WT) and 20 HD mice were randomly assigned to
either an ECS treatment group or a sham control group (10
HD and 10 WT mice per group); ECS was administered
once weekly. HD mice in the ECS group lived significantly
longer, by an average of 2 weeks, compared with HD mice
in the sham-treated group (Fig. 1A). Whereas all of the sham-
treated mice had died by 22 weeks of age, only 30% of the HD
mice subjected to ECS had died. No WT mice in either ECS-
or sham-treated groups died during the 200-day course of this
Because unintended weight loss is a prominent feature in
both HD patients and several transgenic mouse models of
HD including N171-82Q HD mice (10,28), we measured
body weights of all mice twice each week. The effects of
ECS treatment on body weights of WT and HD mice are
shown in Figure 1B. ECS treatment prevented the presympto-
matic weight loss that occurred in sham-treated HD mice. ECS
had no significant effect on body weight in WT mice; mice in
the sham and ECS groups gained weight progressively
throughout the course of the experiment (Fig. 1B).
Loss of motor coordination is another hallmark that devel-
ops early and worsens as the disease progresses in HD patients
and transgenic mouse models of HD (10,29). To determine the
impact of ECS on motor function, we subjected 14-week-old
mice to rotarod testing. Sham-treated HD mice exhibited
highly significant motor dysfunction as indicated by lower
falling latencies (time until falling) and greater numbers of
falls compared with sham-treated WT mice (Fig. 1C and D).
We found that falling latency was significantly greater and
the frequency of falling was significantly less in ECS-treated
compared with sham-treated HD mice (Fig. 1C and D). Collec-
tively, these data demonstrate that ECS treatment promotes
body weight maintenance, ameliorates the severity of motor
deficits and extends survival of N171-82Q HD mice.
ECS ameliorates striatal degeneration in N171-82Q
To determine whether improved motor function and extended
survival of N171-82Q HD mice treated with ECS results from
a slowed progression of the neurodegenerative process, we
performed histological analyses to evaluate the neuronal loss
in the striatum in brain tissue sections from ECS- and sham-
treated HD and WT mice that were killed at 16 weeks of
age (an early symptomatic time point). In N171-82Q HD
mice, the neuronal loss occurs primarily in the striatum and
cerebral cortex resulting in a corresponding enlargement of
the lateral ventricles (10,27). Degenerating neurons in
N171-82Q HD mice are found beginning at approximately
14 weeks of age (27), and so we evaluated the neuronal loss
by NeuN and DARPP-32 immunostaining at 16 weeks of
age when striatal degeneration is prominent. The number of
NeuN-labeled neurons was significantly greater in the striatum
of ECS-treated HD mice compared with sham control HD
mice (Fig. 2A). DARPP-32 is a dopamine- and adenosine
3′:5′-monophosphate-regulated neuronal phosphoprotein and
is expressed selectively in medium spiny projection neurons
(30). The number of neurons labeled with DARPP-32 was
also significantly greater in the striatum of ECS-treated HD
mice in comparison to sham-treated HD mice (Fig. 2B), indi-
cating that ECS rescues the degeneration of medium spiny pro-
jection neurons. Fluoro-Jade C staining was used to detect
degenerating neurons in the striatum; the number of Flouro-
Jade C-labeled degenerating striatal cells was significantly
lower in ECS-treated HD mice compared with sham-treated
HD mice (Fig. 2C).
Progressive striatal and cortical atrophy results in bilateral
ventricular enlargement and flattening of the medial aspect
of the striatum, accompanied by thinning of the cerebral
cortex in HD mice (10). As expected, the lateral ventricle
size in 16-week-old sham control HD mice was significantly
greater than of age-matched WT mice (Fig. 2D). In contrast,
660 Human Molecular Genetics, 2011, Vol. 20, No. 4
the ventricles of 16-week-old ECS-treated HD mice were sig-
nificantly smaller than the ventricles of sham-treated HD mice,
and similar in size to WT mice (Fig. 2D). Collectively, these
findings suggest that ECS attenuates brain atrophy by protect-
ing striatal and cortical neurons against the neurodegenerative
effects of mutant Htt.
ECS reduces Htt protein aggregation in N171-82Q
Mutant Htt forms abnormal intracellular aggregates in degen-
erating neurons in the striatum of N171-82Q HD mice (7–10)
that are associated with neuronal dysfunction and death
(31,32). We therefore determined whether ECS reduced neur-
onal degeneration by suppressing Htt aggregate formation. The
density of Htt aggregates in the striatum, as measured by
image analysis of brain sections immunostained with EM48
antibody, was significantly lower in ECS-treated HD mice in
comparison with sham-treated HD mice (Fig. 3). ECS also
markedly prevented Htt aggregate formation in the cortex of
N171-82Q HD mice (Supplementary Material, Fig. S1). No
Htt aggregate formation was detected in brain sections from
WT mice (data not shown).
ECS normalizes levels of heat-shock proteins in N171-82Q
Heat-shock proteins (Hsps) are protein chaperones that prevent
misfolding and aggregation of newly synthesized mutant pro-
teins and damaged normal proteins (33). Recent findings
suggest that levels of several Hsps decrease in striatal
neurons in HD, possibly as the result of sequestration by
mutant Htt (34,35). Additional findings suggest that mutant
Htt can sequester heat-shock factor 1 (HSF1), a transcription
factor responsible for the induction of many Hsps (36). To
determine whether reduced aggregation may be attributed to
increased expression of Hsps, we measured Hsp70 and
Hsp40 in mice that were given a final ECS or sham treatment
at 13 weeks of age and killed 1 week later. Levels of both
protein chaperones were significantly lower in the striatum
of sham-treated HD mice in comparison with sham-treated
WT mice (Fig. 4A). This decrease in protein chaperones pre-
cedes striatal degeneration that is prominent at 16 weeks
(Fig. 2A–C). ECS treatment markedly increased the levels
of both Hsp70 and Hsp40 in the striatum (Fig. 4A and Sup-
plementary Material, Fig. S2) and cortex (Supplementary
Material, Fig. S3) of HD mice. Note that a trend towards
increased Hsp70 and Hsp40 was present in the striatum of
WT mice; however, significance was not reached. The
elevation of Hsps in the striatum of HD mice was associated
Figure 1. ECS treatment ameliorates motor deficits and extends survival of HD mice. (A) N171-82Q HD mice were treated once weekly with either ECS (n ¼ 10)
or sham control (n ¼ 10) beginning at 2 months of age and deaths were recorded. The Kaplan–Meier analysis revealed a significantly greater survival of mice in
the ECS group (P , 0.05). (B) Body weights of WT and HD mice in the ECS- and sham-treated groups. (C and D) Results of rotarod analysis of motor function
(14 week-old mice) showing falling latency (C) and number of falls (D) for WT and HD mice in ECS- and sham-treated groups. Values are the mean and SEM
(n ¼ 10 mice per group).∗P , 0.05,∗∗P , 0.01.
Human Molecular Genetics, 2011, Vol. 20, No. 4661
with an increase in the HSF1 protein (Fig. 4B). In contrast, the
level of the glucose-regulated protein Grp78 was not signifi-
cantly different in the striatum of ECS-treated HD mice in
comparison with sham-treated HD mice (Fig. 4C). These
results suggest that ECS treatment selectively increases the
expression of Hsps in N171-82Q HD mice, possibly by a
ECS restores BDNF levels in the striatum of N171-82Q
Previous studies have implicated reduced trophic support as a
major pathway contributing to striatal degeneration in HD
(37). The transcription of the bdnf gene has been reported to
be impeded by mutant Htt protein, and BDNF protein levels
are reduced in the striatum of HD patients and transgenic
HD mice (9–11,18). ECS can increase BDNF levels acutely
(within minutes to a few hours) in the hippocampus and cer-
ebral cortex of normal mice, and this effect of ECS is poten-
tiatedby priorECS treatments
determined the effects of ECS on BDNF levels in the striatum
of N171-82Q HD mice that were given a final ECS or sham
treatment at 13 weeks of age and killed 1 week later. BDNF
protein levels, measured by both immunoblot (Fig. 5A) and
enzyme-linked immunosorbent assay (ELISA) (Fig. 5B) ana-
lyses, were significantly lower in the striatum of HD mice in
comparison with WT mice. BDNF levels were significantly
greater in ECS-treated HD mice in comparison with sham-
treated HD mice (Fig. 5A and B).
We next measured striatal levels of activated (phosphory-
lated) Akt and CREB, a kinase and transcription factor
involved in BDNF signaling and BDNF transcription induc-
tion, respectively. The levels of p-Akt and p-CREB were sig-
nificantly lower in the striatum of sham-treated HD mice
compared with WT mice (Fig. 5C and D). In contrast,
levels of p-Akt and p-CREB were similar in the striatum of
ECS-treated HD mice and WT mice (Fig. 5C and D),
suggesting that ECS can prevent the impairment of Akt-
and CREB-mediated signaling caused by mutant Htt. Levels
of phosphorylated tropomyosin-related kinase B (TrkB), the
high-affinity BDNF receptor, were higher in the striatum of
ECS-treated HD mice in comparison with sham-treated HD
mice (Fig. 5E) further suggesting that the activation of
TrkB receptor signaling upon binding of BDNF is involved
in the increase of p-Akt and p-CREB in the striatum of ECS-
treated HD mice.
Figure 2. ECS treatment attenuates the degeneration of striatal neurons in HD mice. (A) Representative images of NeuN-stained cells (upper micrographs; scale
bar ¼ 250 mm) and results of counts of NeuN-positive cells (lower graph) in 16-week-old WT and N171-82Q HD mice in ECS- and sham-treated groups,∗∗P ,
0.01. (B) Representative images showing DARRP-2 immunoreactivity (red; scale bar ¼ 20 mm) and results of densitometric analysis (right graph) in 16-week-old
N171-82Q HD mice in ECS- and sham-treated groups. Values are the mean and SEM (n ¼ 9–10 mice per group).∗P , 0.05. (C) Representative images of
FluorJade C (FJ-C)-stained (degenerating neurons) in the striatum (micrographs at left; scale bar ¼ 250 mm) and results of counts of FJ-C stained cells
(graph) in 16-week-old WT and HD mice in ECS- and sham-treated groups.∗∗∗P , 0.001. (D) Representative images of cresyl violet-stained coronal brain sec-
tions (left) and results of measurements of the area of the lateral ventricle (graph) in 16-week-old WT and HD mice in ECS- and sham-treated groups.∗∗∗P ,
0.001. Scale bar ¼ 250 mm.
662 Human Molecular Genetics, 2011, Vol. 20, No. 4
HD is a progressive neurodegenerative disease for which there
is no effective therapy. Because HD is caused by a mutation in
the gene encoding Htt, genetic testing can identify patients
before they become symptomatic, thus offering the possibility
of early interventions that delay or prevent the onset of the
disease. In the present study, we show that once-weekly
ECS treatments delay disease onset and improve survival by
an average of 2 weeks which is comparable with the reported
increase in survival in N171-82Q HD mice that were either
maintained on an intermittent fasting dietary restriction
regimen (10) or treated with antidepressant drugs (38,39). His-
tological analyses demonstrated a reduction in the neuron loss
in the striatum of ECS-treated HD mice compared with sham-
treated HD mice. These results in an animal model of HD
suggest that ECS treatment can counteract the pathogenic
actions of mutant Htt, thereby preserving the viability and
function of striatal neurons.
To elucidate the mechanism by which ECS treatment ame-
liorates cellular pathology and extends lifespan, we examined
neuroprotective proteins that inhibit apoptotic biochemical
cascades and preserve the cellular ability to adapt to stress.
ECS treatment resulted in elevated levels of the protein cha-
perones Hsp70 and Hsp40 in the striatum of HD mice.
Studies in which levels of Hsp70 or Hsp40 are selectively
increased or decreased have shown that these two chaperones
can protect neurons against insults relevant to HD including
excitotoxins, metabolic stress and mutant Htt (40,41).
The expanded polyglutamine stretch in mutant Htt is
thought to trigger a conformational change that leads to
partial unfolding or misfolding which, if not corrected by mol-
ecular chaperones, can lead to abnormal proteolysis and
protein aggregation (42,43). Histopathological comparison
showed that ECS treatment resulted in a significant reduction
in striatal and cortical Htt aggregation. Misfolding and aggre-
gation of mutant Htt are therapeutic targets since they are early
molecular events in the pathogenic cascades that underlie the
neurological dysfunction in transgenic HD mice (32). A
variety of molecular chaperones have been demonstrated to
exert therapeutic effects against various experimental models
of the polyglutamine diseases, including HD (44–46). Here
we showed that once-weekly ECT treatment increases Hsp70
and Hsp40 that likely played a significant role in suppressing
Htt misfolding and aggregation. Indeed, we found that the
ECS treatment reduces Htt aggregation in striatal (Fig. 3)
and cortical (data not shown) cells of HD mice suggesting
that ECS interrupts the disease process at an early stage. The
ECS-induced increase of Hsp70 and Hsp40 is likely mediated
by HSF1, a stress-responsive transcriptional regulator that has
been shown to suppress polyglutamine aggregate formation in
cellular and mouse models (47).
HD mice compared with WT mice, and that BDNF levels were
significantly increased in HD mice that had been maintained on
ticity and neuronal survival in many brain regions including
(11–14), can protect striatal and cortical neurons in experimen-
tal models of HD. Because BDNF transcription has been
reported to be impeded by the misfolded Htt protein and
because Hsps reduce the accumulation of misfolded Htt
protein, our data suggest that elevation of Hsps may contribute
in part to the restoration of the BDNF level in ECS-treated
HD mice. Furthermore, as the majority of striatal BDNF is syn-
gation of cortical aggregate formation may lessen the HD’s
adverse effects on the basal ganglia.
The elevation of BDNF levels may mediate, at least in part,
the retardation of disease onset and extension of survival by
ECS in N171-82Q HD mice. Consistent with the latter possi-
bility, it was reported that paroxetine and seratraline, two
other anti-depressant treatments that increase BDNF levels in
the striatum and cortex of HD mice, also delay disease onset
and extend survival in N171-82Q HD mice (38,39). BDNF
may protect neurons against excitotoxic, metabolic and oxi-
dative stress believed to be involved in the death of neurons
in HD. Indeed, BDNF can protect neurons against glutamate
receptor-mediated excitotoxicity (14,49) energetic/mitochon-
drial stress (12,13) and oxidative insults (50). By maintaining
the survival and function of striatal neurons, BDNF levels
could improve motor control in HD mice as reduction in
BDNF levels advances the age of onset and exacerbates the
severity of motor dysfunction (16,18). Hence, although ECS
treatment may induce the expression of a plethora of
plasticity-related genes (51), the elevation of BDNF is likely
responsible for ameliorating the behavioral and neuropatholo-
gical phenotype in N171-82Q HD mice.
Apart from protecting vulnerable neurons, ECS has been
shown to facilitate neurogenesis through upregulation of
BDNF and other growth factors (52). Although not addressed
in the present study, it is possible that increased neurogenesis
Figure 3. ECS treatment attenuates Htt aggregation in striatum of HD mice.
Representative images showing huntingtin (Htt) immunoreactive aggregates
in the striatum (red; left micrographs; scale bar ¼ 250 mm) stained with
EM48 antibody and results of densitometric analysis of EM48 immunoreactiv-
ity (right graph) in 16-week-old N171-82Q HD mice in ECS- and sham-treated
groups. Values are the mean and SEM (n ¼ 9–10 mice per group).∗∗P ,
Human Molecular Genetics, 2011, Vol. 20, No. 4663
which functions to replace lost or damaged striatal neurons
may contribute to ECS-induced beneficial effects. It has
been demonstrated that induction of neurogenesis can slow
disease progression in transgenic HD mice (15). One func-
tional consequence of neurogenesis is learning and memory
(53), and impaired learning has also been described in differ-
ent transgenic mouse models of HD (54). Previous studies
showed that ECS treatment increased the total number of
synapses in adult male rat hippocampus (55,56). Because a
of transgenic HD mice (57) and because this neurotrophin has
been shown to rescue the deficits in long-term potentiation of
synaptic transmission (a cellular correlate of learning and
memory) in hippocampal slices from transgenic HD mice (58),
cognitive impairments in transgenic HD mice.
Interestingly, ECS did not have significant effects on levels
of Hsp70, Hsp40 and BDNF in the striatum of WT mice,
although there were clear trends towards elevated levels of
each of these proteins. Previous studies have shown that
BDNF mRNA levels are increased acutely (hours to a few
days) in the hippocampus following ECS (59). Other studies
have found that BDNF mRNA levels in the hippocampus are
elevated 2-fold in rats that had received daily ECS treatments
for a 10-day period (60). Another study found that BDNF
protein levels were significantly increased in the cortex and
striatum of rats after 10 daily ECS treatments (60). In our
study, the mice were treated with ECS once weekly for 8
weeks using a 50 mA, 0.2 s ECS stimulus. Our ECS treatment
was therefore less frequent than previous studies, which could
explain the lesser effect of our treatment regimen on BDNF
levels compared with more frequent ECS treatments. Striatal
neurons in HD mice may be more sensitive to a low ECS treat-
ment because of their lower threshold for excitability, and
hence exhibit a greater increase in levels of BDNF and
In addition to mitigating both gross brain and neuronal
atrophy, ECS treatment also ameliorated the progressive
body weight loss in N171-82Q HD mice. The basis for the
weight loss in HD mice is not yet clear. BDNF and its receptor,
TrkB, play prominent roles in food intake and energy metab-
olism regulation through central mechanisms involving the
hypothalamus (61). The potential role of BDNF in regulation
of energy metabolism was first discovered through generation
of BDNF+mice which display an obese phenotype (62,63).
Subsequently, mutations in bdnf and trkB have been identified
in some obese patients (64,65). Genetic ablation of bdnf in the
hypothalamus of adult mice results in hyperphagic behavior
Figure 4. ECS elevates levels of adaptive stress response proteins in the striatum of HD mice. (A) A representative immunoblot (left) and results of densitometric
analysis (right) of Hsp70 and Hsp40 protein levels in striatal tissue samples from ECS- and sham-treated HD and WT mice.∗P , 0.05. (B and C) An immunoblot
(upper) and results of densitometric analysis (lower) of HSF-1 (B) and Grp78 (C) protein levels in striatal tissue samples from the indicated groups of mice.
Values are the mean and SEM (n ¼ 8–10 mice per group).∗P , 0.05.
664 Human Molecular Genetics, 2011, Vol. 20, No. 4
and obesity (66). Emerging evidence suggests that disturbed
functions of the hypothalamus may contribute to some signs
and symptoms associated with metabolic alterations in HD
patients (67). Further studies are needed to examine whether
the body weight loss and its amelioration by ECS involve
altered expression of BDNF in the hypothalamus of HD mice.
A functional BDNF polymorphism (BDNF Val66Met) was
reported to influence the vulnerability to various psychiatric
disorders (68). There has been a resurgence of interest in the
use of ECS for the treatment of drug-refractive psychiatric dis-
orders, and it is considered safe and effective for the treatment
of depressionin the elderly,
co-morbidities (56). ECS treatments often result in long-
lasting clinical improvements in psychiatric symptoms which
are correlated with the increased BDNF level (69–71).
Several reports describe the beneficial effects of ECS in reliev-
ing depression in HD patients (23,72–74) who, in general,
have higher suicide rates relative to those with other medical
and neurodegenerative diseases (75,76). However, there have
been no controlled studies of ECS treatment in symptomatic
HD patients, nor any attempts to delay the onset of HD with
periodic ECS treatments. Our preclinical findings demonstrate
for the first time that ECS treatment slows the progression of
the neurodegenerative process caused by mutant Htt in an
animal model of HD. ECS treatment resulted in increase in
the expression of several adaptive cellular stress response pro-
teins which may promote neuronal survival and plasticity, and
so forestall the neurodegenerative process resulting in a delay
in the disease onset and life extension. The present findings
have significant implications for preventive treatment strat-
egies for individuals that carry the mutant Htt gene.
MATERIALS AND METHODS
Mice and ECS treatment
HD-N171-82Q mice were purchased from the Jackson Labora-
tories (Bar Harbor, ME, USA) and were maintained on the
B6C3F1 background; offspring were identified by PCR analy-
sis using genomic DNA extracted from tail biopsies to dis-
tinguish transgene-bearing mice from their WT littermates
(27). Mice were maintained under usual laboratory conditions
that included ad libitum feeding and drinking, in a
non-enriched environment (77). Experiments were performed
on 2-month-old male mice that were assigned randomly to
control and ECS treatment groups. All procedures were
approved by the National Institute on Aging Animal Care
and Use Committee. ECS was delivered to mice under isoflur-
ane inhalation anesthesia once a week via bilateral ear clip
electrodes using the Ugo Basile, ECS Unit 7801. The stimulus
Figure 5. ECS ameliorates deficits in levels of BDNF, and activated Akt and CREB, in the striatum of HD mice. (A) A representative immunoblot (left) and
results of densitometric analysis (right) of BDNF protein levels in striatal tissue samples from ECS- and sham-treated HD and WT mice.∗P , 0.001. (B) BDNF
protein levels, measured by ELISA analysis, in samples of striatal tissue from ECS- and sham-treated HD and WT mice.∗P , 0.05. (C) A representative immu-
noblot (left) and results of densitometric analysis (right) of phospho-Akt protein levels in striatal tissue samples from ECS- and sham-treated HD and WT mice.
∗P , 0.05. (D) A representative immunoblot (left) and results of densitometric analysis of phospho-CREB protein (right) levels in striatal tissue samples from
ECS- and sham-treated HD and WT mice.∗P , 0.05. (E) A representative immunoblot (upper) and results of densitometric analysis of phospho-TrkB protein
(lower) levels in striatal tissue samples from ECS- and sham-treated HD and WT mice. Values are the mean and SEM (n ¼ 8–10 mice per group).∗P , 0.05.
Human Molecular Genetics, 2011, Vol. 20, No. 4665
current was 50 mA and the stimulus duration was 0.2 s (78).
The presence of tonic seizures immediately after the shock
was confirmed by observing the extension of all limbs and
forward head extension that normally last for about 10–15 s
in each cohort regardless of the genotype. The sham groups
were handled identically to the ECS-treated rats except no
current was applied. ECS- and sham-treated mice were
returned to their cages 10 min afterwards.
Motor coordination and balance were evaluated at weekly
intervals throughout the course of the study using an acceler-
ating rotary rod apparatus (Columbus Instrument, OH, USA)
as described previously (10). To exclude the possibility that
ECS may negatively impact motor performance, rotarod per-
formance was performed 3 days after ECS. Mice were
trained to use the rotarod apparatus during a 2 min trial
(4 rpm) on the day before the first day of testing. On test
days, mice were placed on the rotarod for three trials for a
maximal 4min at accelerating speeds from 4 to 40 rpm
and maintenance at 40 rpm after 4 min. Each trial was
separated by a 30 min rest period to alleviate stress and
fatigue. Latency to fall and falling times for each mouse
were recorded by a trained observer blind to the treatment
group of the mice.
Once motor symptoms appeared the HD mice were examined
twice daily in the early morning and late afternoon by an
investigator blinded as to treatment group of the mice. Mice
unable to right themselves after being placed on their backs,
and unable to initiate movement after being gently prodded
for 10 min (79) were euthanized; their age at this point was
considered the age of death. Deaths that occurred overnight
were recorded the next morning.
Tissue preparation and histologic analysis
Immediately after being anesthetized with an overdose of iso-
flurane, mice were perfused transcardially with saline, fol-
lowed by 4% paraformaldehyde (PFA) in PBS (pH 7.4).
Brains were post-fixed in 4% PFA for 24 h, and then cryopro-
tected in 30% sucrose/PBS for 48 h. Serial coronal sections
(10 mm thickness) cut through the entire striatum with a freez-
ing microtome (Microm HM 505 N) were collected on slides.
Nissl and Fluorojade C staining were performed as previously
described (80) to determine surviving and degenerating
neurons, respectively. For Fluoro-Jade staining, the slides
were immersed for 3 min in 100% ethanol, for 1 min in 70%
ethanol, and for 1 min in distilled water and then incubated
in a solution containing 0.01% Fluoro-Jade (Histo-Chem,
Inc., Jefferson, AR, USA) and 0.1% acetic acid (1:10) for
30 min on a shaker. After three 10 min washes, the slides
were cover slipped.
Serially cut coronal tissue sections were blocked with 5%
normal serum in 0.1% Triton X-100 in PBS for 30 min at
room temperature followed by incubation overnight at 48C
with primary antibodies against N-terminal Htt protein
(EM48, Chemicon; 1:400 dilution), NeuN (Chemicon; 1:400
dilution) and DARPP-32 (Abcam; 1;500 dilution). Tissue sec-
tions were incubated with Alexa568- or Alexa488-conjugated
secondary antibodies (1:200, Molecular Probes) appropriate
for the specific primary antibodies. The sections were then
washed with 0.05% Tween-20 in phosphate-buffered saline
for 1 h and counterstained with 4′,6′-diamidino-2-phenylindole
(50 ng/ml) for 30 s, washed and mounted in FluorSave medium
Quantification of Htt aggregates and neurons
Images of EM48-positive neuronal inclusions and DARPP-32,
Nissl or Fluorojade C-stained neurons were obtained by
scanning 10–12 coronal sections spread over the anterior–
posterior extent of the striatum (inter-section distance:
400 mm), using a 20× objective on a Nikon 80i Research
Upright Microscope equipped with image acquisition software
(QimagingRetiga 2000). All images were segmented using the
same light threshold, mask smoothing and object size filters.
Total area of pixel intensity was measured with the automated
measurement tools in IP lab software (BD Biosciences
Bio-imaging). The total density was averaged and expressed
as normalized, corrected OD. Labeled cells were counted
throughout the depth of the section for four adjacent fields
of each section. All brain specimens were coded and analyses
were performed by an investigator blinded as to the genotype
and treatment group of the mice.
Methods for protein quantification, electrophoretic separation
and transfer to nitrocellulose membranes were described pre-
viously (62). Membranes were incubated in blocking solution
(5% milk in Tween Tris-buffered saline; TTBS) overnight at
48C followed by a 1 h incubation in primary antibody
diluted in blocking solution at room temperature. Membranes
were then incubated for 1 h in secondary antibody conjugated
to horseradish peroxidase (Vector Laboratories) and bands
were visualized using a chemiluminiscence detection kit
(ECL, Amersham). Membranes were stripped and re-probed
with the actin antibody to verify and normalize protein
loading (50 mg total protein, unless stated otherwise). For
immunodetection of blots, enhanced chemiluminescence
(ECL, Amersham) was applied. Immunoreactive bands were
quantified using NIH Image software. Information on the
primary antibodies used in this study, including the source,
dilution and molecular weight of the antigen, can be found
in Supplementary Material, Table S1.
Kaplan–Meier survival data were analyzed using the log-rank
test for trend. All other data were analyzed using one-way
666 Human Molecular Genetics, 2011, Vol. 20, No. 4
ANOVA with Dunnett’s post hoc test for pairwise compari-
sons or Student’s t-test as appropriate. These statistical ana-
lyses were performed using GraphPad Prism version 5.00 for
Windows (GraphPad Software, San Diego, CA, USA).
P-values ≤ 0.05 were considered significant.
Supplementary Material is available at HMG online.
Conflict of Interest statement. None declared.
This research was supported by the Intramural Research
Program of the National Institute on Aging of the National
Institutes of Health, and by NIH grant (1R21NS066265-01)
1. Haddad, M.S. and Cummings, J.L. (1997) Huntington’s disease. Psychiatr.
Clin. North Am., 20, 791–807.
2. Gusella, J.F., Wexler, N.S., Conneally, P.M., Naylor, S.L., Anderson,
M.A., Tanzi, R.E., Watkins, P.C., Ottina, K., Wallace, M.R., Sakaguchi,
A.Y. et al. (1983) A polymorphic DNA marker genetically linked to
Huntington’s disease. Nature, 306, 234–238.
3. Wexler, N.S., Rose, E.A. and Housman, D.E. (1991) Molecular
approaches to hereditary diseases of the nervous system: Huntington’s
disease as a paradigm. Annu. Rev. Neurosci., 14, 503–529.
4. Velier, J., Kim, M., Schwarz, C., Kim, T.W., Sapp, E., Chase, K., Aronin,
N. and DiFiglia, M. (1998) Wild-type and mutant huntingtins function in
vesicle trafficking in the secretory and endocytic pathways. Exp. Neurol.,
5. Smith, R., Brundin, P. and Li, J.Y. (2005) Synaptic dysfunction in
Huntington’s disease: a new perspective. Cell Mol. Life Sci., 62, 1901–
6. Zuccato, C., Valenza, M. and Cattaneo, E. (2010) Molecular mechanisms
and potential therapeutical targets in Huntington’s disease. Physiol. Rev.,
7. Cooper, J.K., Schilling, G., Peters, M.F., Herring, W.J., Sharp, A.H.,
Kaminsky, Z., Masone, J., Khan, F.A., Delanoy, M., Borchelt, D.R. et al.
(1998) Truncated N-terminal fragments of huntingtin with expanded
glutamine repeats form nuclear and cytoplasmic aggregates in cell culture.
Hum. Mol. Genet., 7, 783–790.
8. Martindale, D., Hackam, A., Wieczorek, A., Ellerby, L., Wellington, C.,
McCutcheon, K., Singaraja, R., Kazemi-Esfarjani, P., Devon, R., Kim,
S.U. et al. (1998) Length of huntingtin and its polyglutamine tract
influences localization and frequency of intracellular aggregates. Nat.
Genet., 18, 150–154.
9. Zuccato, C., Marullo, M., Conforti, P., MacDonald, M.E., Tartari, M. and
Cattaneo, E. (2008) Systematic assessment of BDNF and its receptor
levels in human cortices affected by Huntington’s disease. Brain Pathol.,
10. Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X.J. and Mattson, M.P. (2003)
Dietary restriction normalizes glucose metabolism and BDNF levels,
slows disease progression, and increases survival in huntingtin mutant
mice. Proc. Natl Acad. Sci. USA, 100, 2911–2916.
11. Gharami, K., Xie, Y., An, J.J., Tonegawa, S. and Xu, B. (2008)
Brain-derived neurotrophic factor over-expression in the forebrain
ameliorates Huntington’s disease phenotypes in mice. J. Neurochem., 105,
12. Cheng, B. and Mattson, M.P. (1994) NT-3 and BDNF protect CNS
neurons against metabolic/excitotoxic insults. Brain Res., 640, 56–67.
13. Nakao, N., Kokaia, Z., Odin, P. and Lindvall, O. (1995) Protective effects
of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured
striatal neurons. Exp. Neurol., 131, 1–10.
(1999) Brain-derived neurotrophic factor-mediated protection of striatal
by adenoviral gene transfer. Hum. Gene Ther., 10, 2987–2997.
15. Cho, S.R., Benraiss, A., Chmielnicki, E., Samdani, A., Economides, A.
and Goldman, S.A. (2007) Induction of neostriatal neurogenesis slows
disease progression in a transgenic murine model of Huntington disease.
J. Clin. Invest., 117, 2889–2902.
16. Canals, J.M., Pineda, J.R., Torres-Peraza, J.F., Bosch, M., Martin-Ibanez,
R., Munoz, M.T., Mengod, G., Ernfors, P. and Alberch, J. (2004)
Brain-derived neurotrophic factor regulates the onset and severity of
motor dysfunction associated with enkephalinergic neuronal degeneration
in Huntington’s disease. J. Neurosci., 24, 7727–7739.
17. Nucifora, F.C. Jr, Sasaki, M., Peters, M.F., Huang, H., Cooper, J.K.,
Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J., Dawson, V.L. et al.
(2001) Interference by huntingtin and atrophin-1 with cbp-mediated
transcription leading to cellular toxicity. Science, 291, 2423–2428.
18. Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L.,
Cataudella, T., Leavitt, B.R., Hayden, M.R., Timmusk, T. et al. (2003)
Huntingtin interacts with REST/NRSF to modulate the transcription of
NRSE-controlled neuronal genes. Nat. Genet., 35, 76–83.
19. Spires, T.L., Grote, H.E., Varshney, N.K., Cordery, P.M., van Dellen, A.,
Blakemore, C. and Hannan, A.J. (2004) Environmental enrichment
rescues protein deficits in a mouse model of Huntington’s disease,
indicating a possible disease mechanism. J. Neurosci., 24, 2270–2276.
20. Payne, N.A. and Prudic, J. (2009) Electroconvulsive therapy: part I. A
perspective on the evolution and current practice of ECT. J. Psychiatr.
Pract., 15, 346–368.
21. Sutor, B. and Rasmussen, K.G. (2008) Electroconvulsive therapy for
agitation in Alzheimer disease: a case series. J. ECT, 24, 239–241.
22. Moellentine, C., Rummans, T., Ahlskog, J.E., Harmsen, W.S., Suman,
V.J., O’Connor, M.K., Black, J.L. and Pileggi, T. (1998) Effectiveness of
ECT in patients with parkinsonism. J. Neuropsychiatry Clin. Neurosci.,
23. Lewis, C.F., DeQuardo, J.R. and Tandon, R. (1996) ECT in genetically
confirmed Huntington’s disease. J. Neuropsychiatry Clin. Neurosci., 8,
24. Beale, M.D., Kellner, C.H., Gurecki, P. and Pritchett, J.T. (1997) ECT for
the treatment of Huntington’s disease: a case study. Convuls. Ther., 13,
25. Nibuya, M., Morinobu, S. and Duman, R.S. (1995) Regulation of BDNF
and trkB mRNA in rat brain by chronic electroconvulsive seizure and
antidepressant drug treatments. J. Neurosci., 15, 7539–7547.
26. Altar, C.A., Whitehead, R.E., Chen, R., Wortwein, G. and Madsen, T.M.
(2003) Effects of electroconvulsive seizures and antidepressant drugs on
brain-derived neurotrophic factor protein in rat brain. Biol. Psychiatry, 54,
27. Schilling, G., Becher, M.W., Sharp, A.H., Jinnah, H.A., Duan, K., Kotzuk,
J.A., Slunt, H.H., Ratovitski, T., Cooper, J.K., Jenkins, N.A. et al. (1999)
Intranuclear inclusions and neuritic aggregates in transgenic mice
expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet.,
28. Djousse, L., Knowlton, B., Cupples, L.A., Marder, K., Shoulson, I. and
Myers, R.H. (2002) Weight loss in early stage of Huntington’s disease.
Neurology, 59, 1325–1330.
29. Thompson, P.D., Berardelli, A., Rothwell, J.C., Day, B.L., Dick, J.P.,
Benecke, R. and Marsden, C.D. (1988) The coexistence of bradykinesia
and chorea in Huntington’s disease and its implications for theories of
basal ganglia control of movement. Brain, 111, 223–244.
30. Hemmings, H.C. Jr and Greengard, P. (1986) DARPP-32, a
dopamine-regulated phosphoprotein. Prog. Brain Res., 69, 149–159.
31. Moulder, K.L., Onodera, O., Burke, J.R., Strittmatter, W.J. and Johnson,
E.M. Jr. (1999) Generation of neuronal intranuclear inclusions by
polyglutamine-GFP: analysis of inclusion clearance and toxicity as a
function of polyglutamine length. J. Neurosci., 19, 705–715.
32. Davies, S.W., Turmaine, M., Cozens, B.A., DiFiglia, M., Sharp, A.H.,
Ross, C.A., Scherzinger, E., Wanker, E.E., Mangiarini, L. and Bates, G.P.
(1997) Formation of neuronal intranuclear inclusions underlies the
neurological dysfunction in mice transgenic for the HD mutation. Cell, 90,
33. Wickner, S., Maurizi, M.R. and Gottesman, S. (1999) Posttranslational
quality control: folding, refolding, and degrading proteins. Science, 286,
Human Molecular Genetics, 2011, Vol. 20, No. 4667
34. Hay, D.G., Sathasivam, K., Tobaben, S., Stahl, B., Marber, M., Mestril,
R., Mahal, A., Smith, D.L., Woodman, B. and Bates, G.P. (2004)
Progressive decrease in chaperone protein levels in a mouse model of
Huntington’s disease and induction of stress proteins as a therapeutic
approach. Hum. Mol. Genet., 13, 1389–1405.
35. Muchowski, P.J., Schaffar, G., Sittler, A., Wanker, E.E., Hayer-Hartl,
M.K. and Hartl, F.U. (2000) Hsp70 and hsp40 chaperones can inhibit
self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc.
Natl Acad. Sci. USA, 97, 7841–7846.
36. Chiang, M.C., Chen, H.M., Lai, H.L., Chen, H.W., Chou, S.Y., Chen,
C.M., Tsai, F.J. and Chern, Y. (2009) The A2A adenosine receptor rescues
the urea cycle deficiency of Huntington’s disease by enhancing the activity
of the ubiquitin-proteasome system. Hum. Mol. Genet., 18, 2929–2942.
37. Strand, A.D., Baquet, Z.C., Aragaki, A.K., Holmans, P., Yang, L., Cleren,
C., Beal, M.F., Jones, L., Kooperberg, C., Olson, J.M. et al. (2007)
Expression profiling of Huntington’s disease models suggests that
brain-derived neurotrophic factor depletion plays a major role in striatal
degeneration. J. Neurosci., 27, 11758–11768.
38. Duan, W., Guo, Z., Jiang, H., Ladenheim, B., Xu, X., Cadet, J.L. and
Mattson, M.P. (2004) Paroxetine retards disease onset and progression in
Huntingtin mutant mice. Ann. Neurol., 55, 590–594.
39. Duan, W., Peng, Q., Masuda, N., Ford, E., Tryggestad, E., Ladenheim, B.,
Zhao, M., Cadet, J.L., Wong, J. and Ross, C.A. (2008) Sertraline slows
disease progression and increases neurogenesis in N171–82Q mouse
model of Huntington’s disease. Neurobiol. Dis., 30, 312–322.
40. Lai, Y., Du, L., Dunsmore, K.E., Jenkins, L.W., Wong, H.R. and Clark,
R.S. (2005) Selectively increasing inducible heat shock protein 70 via
TAT-protein transduction protects neurons from nitrosative stress and
excitotoxicity. J. Neurochem., 94, 360–366.
41. Tantucci, M., Mariucci, G., Taha, E., Spaccatini, C., Tozzi, A., Luchetti,
E., Calabresi, P. and Ambrosini, M.V. (2009) Induction of heat shock
protein 70 reduces the alteration of striatal electrical activity caused by
mitochondrial impairment. Neuroscience, 163, 735–740.
42. Wanker, E.E. (2000) Protein aggregation and pathogenesis of
Huntington’s disease: mechanisms and correlations. J. Biol. Chem., 381,
43. Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl,
M.K., Hartl, F.U. and Wanker, E.E. (2001) Geldanamycin activates a heat
shock response and inhibits huntingtin aggregation in a cell culture model
of Huntington’s disease. Hum. Mol. Genet., 10, 1307–1315.
44. Warrick, J.M., Chan, H.Y., Gray-Board, G.L., Chai, Y., Paulson, H.L. and
Bonini, N.M. (1999) Suppression of polyglutamine-mediated
neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat.
Genet., 23, 425–428.
45. Wacker, J.L., Zareie, M.H., Fong, H., Sarikaya, M. and Muchowski, P.J.
(2004) Hsp70 and Hsp40 attenuate formation of spherical and annular
polyglutamine oligomers by partitioning monomer. Nat. Struct. Mol. Biol.,
46. Vacher, C., Garcia-Oroz, L. and Rubinsztein, D.C. (2005) Overexpression
of yeast hsp104 reduces polyglutamine aggregation and prolongs survival
of a transgenic mouse model of Huntington’s disease. Hum. Mol. Genet.,
47. Mejimoto, M., Takaki, E., Hayashi, T., Kitaura, Y., Tanaka, Y., Inouye, S.
and Nakai, A. (2005) Active HSF1 significantly suppresses polyglutamine
aggregate formation in cellular and mouse models. J. Biol. Chem., 280,
48. Altar, C.A., Cai, N., Bliven, T., Juhasz, M., Conner, J.M., Acheson, A.L.,
Lindsay, R.M. and Wiegand, S.J. (1997) Anterograde transport of
brain-derived neurotrophic factor and its role in the brain. Nature, 389,
49. Duan, W., Guo, Z. and Mattson, M.P. (2001) Brain-derived neurotrophic
factor mediates an excitoprotective effect of dietary restriction in mice.
J. Neurochem., 76, 619–626.
50. Mattson, M.P., Lovell, M.A., Furukawa, K. and Markesbery, W.R. (1995)
Neurotrophic factors attenuate glutamate-induced accumulation of
peroxides, elevation of intracellular Ca2+ concentration, and
neurotoxicity and increase antioxidant enzyme activities in hippocampal
neurons. J. Neurochem., 65, 1740–1751.
51. Sun, W., Park, K.W., Choe, J., Rhyu, I.J., Kim, I.H., Park, S.K., Choi, B.,
Choi, S.H., Park, S.H. and Kim, H. (2005) Identification of novel
electroconvulsive shock-induced and activity-dependent genes in the rat
brain. Biochem. Biophys. Res. Commun., 327, 848–856.
52. Ploski, J.E., Newton, S.S. and Duman, R.S. (2006) Electroconvulsive
seizure-induced gene expression profile of the hippocampus dentate gyrus
granule cell layer. J. Neurochem., 99, 1122–1132.
53. Deng, W., Aimone, J.B. and Gage, F.H. (2010) New neurons and new
memories: how does adult hippocampal neurogenesis affect learning and
memory? Nat. Rev. Neurosci., 11, 339–350.
54. Van Raamsdonk, J.M., Pearson, J., Slow, E.J., Hossain, S.M., Leavitt, B.R.
and Hayden, M.R. (2005) Cognitive dysfunction precedes neuropathology
and motor abnormalities in the YAC128 mouse model of Huntington’s
disease. J. Neurosci., 25, 4169–4180.
55. Stewart, C. and Reid, I. (1993) Electroconvulsive stimulation and synaptic
plasticity in the rat. Brain Res., 620, 139–141.
56. Chen, F., Madsen, T.M., Wegener, G. and Nyengaard, J.R. (2009)
Repeated electroconvulsive seizures increase the total number of synapses
in adult male rat hippocampus. Eur. Neuropsychopharmacol., 19, 329–
57. Lynch, G., Kramar, E.A., Rex, C.S., Jia, Y., Chappas, D., Gall, C.M. and
Simmons, D.A. (2007) Brain-derived neurotrophic factor restores synaptic
plasticity in a knock-in mouse model of Huntington’s disease.
J. Neurosci., 27, 4424–4434.
58. Simmons, D.A., Rex, C.S., Palmer, L., Pandyarajan, V., Fedulov, V., Gall,
C.M. and Lynch, G. (2009) Up-regulating BDNF with an ampakine
rescues synaptic plasticity and memory in Huntington’s disease knockin
mice. Proc. Natl Acad. Sci. USA, 106, 4906–4911.
59. Zetterstro ¨m, T.S., Pei, Q. and Grahame-Smith, D.G. (1998) Repeated
electroconvulsive shock extends the duration of enhanced gene expression
for BDNF in rat brain compared with a single administration. Brain Res.
Mol. Brain Res., 57, 106–110.
60. Altar, C.A., Whitehead, R.E., Chen, R., Wo ¨rtwein, G. and Madsen, T.M.
(2003) Effects of electroconvulsive seizures and antidepressant drugs on
brain-derived neurotrophic factor protein in rat brain. Biol. Psychiatry, 54,
61. Xu, B.E.H., Goulding, K., Zang, D., Cepoi, R.D., Cone, K.R., Jones, L.H.,
Tecott, L.H. and Reichardt, L.F. (2003) Brain-derived neurotrophic factor
regulates energy balance downstream of melanocortin-4 receptor. Nat.
Neurosci., 6, 736–742.
62. Kernie, S.G., Liebl, D.J. and Parada, L.F. (2000) BDNF regulates eating
behavior and locomotor activity in mice. EMBO J., 19, 1290–1300.
63. Rios, M., Fan, G., Fekete, C., Kelly, J., Bates, B., Kuehn, R., Lechan, R.M.
and Jaenisch, R. (2001) Conditional deletion of brain-derived neurotrophic
factor in the postnatal brain leads to obesity and hyperactivity. Mol.
Endocrinol., 15, 1748–1757.
64. Yeo, G.S., Connie Hung, C.C., Rochford, J., Keogh, J., Gray, J.,
Sivaramakrishnan, S., O’Rahilly, S. and Farooqi, I.S. (2004) A de novo
mutation affecting human TrkB associated with severe obesity and
developmental delay. Nat. Neurosci., 7, 1187–1189.
65. Friedel, S., Horro, F.F., Wermter, A.K., Geller, F., Dempfle, A.,
Reichwald, K., Smidt, J., Bronner, G., Konrad, K., Herpertz-Dahlmann, B.
et al. (2005) Mutation screen of the brain derived neurotrophic factor gene
(BDNF): identification of several genetic variants and association studies
in patients with obesity eating disorders and attention-deficit/hyperactivity
disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet., 132, 96–99.
66. Unger, T.J., Calderon, G.A., Bradley, L.C., Sena-Esteves, M. and Rios, M.
(2007) Selective deletion of Bdnf in the ventromedial and dorsomedial
hypothalamus of adult mice results in hyperphagic behavior and obesity.
J. Neurosci., 27, 14265–14274.
67. Aziz, N.A., Swaab, D.F., Pijl, H. and Roos, R.A. (2007) Hypothalamic
dysfunction and neuroendocrine and metabolic alterations in Huntington’s
disease: clinical consequences and therapeutic implications. Rev.
Neurosci., 18, 223–251.
68. Pregelj, P., Nedic, G., Paska, A.V., Zupanc, T., Nikolac, M., Balaz ˇic, J.,
Tomori, M., Komel, R., Seler, D.M. and Pivac, N. (2010) The association
between brain-derived neurotrophic factor polymorphism (BDNF
Val66Met) and suicide. J Affect Disord. [Epub ahead of print, 26 July].
69. Bocchio-Chiavetto, L., Zanardini, R., Bortolomasi, M., Abate, M., Segala,
M., Giacopuzzi, M., Riva, M.A., Marchina, E., Pasqualetti, P., Perez, J.
et al. (2006) Electroconvulsive therapy (ECT) increases serum brain
derived neurotrophic factor (BDNF) in drug resistant depressed patients.
Eur. Neuropsychopharmacol., 16, 620–624.
70. Marano, C.M., Phatak, P., Vemulapalli, U.R., Sasan, A., Nalbandyan,
M.R., Ramanujam, S., Soekadar, S., Demosthenous, M. and Regenold,
W.T. (2007) Increased plasma concentration of brain-derived neurotrophic
668 Human Molecular Genetics, 2011, Vol. 20, No. 4
factor with electroconvulsive therapy: a pilot study in patients with major Download full-text
depression. J. Clin. Psychiatry, 68, 512–517.
71. Taylor, S.M. (2008) Electroconvulsive therapy, brain-derived
neurotrophic factor, and possible neurorestorative benefit of the clinical
application of electroconvulsive therapy. J. ECT, 24, 160–165.
72. Piccinni, A., Del Debbio, A., Medda, P., Bianchi, C., Roncaglia, I., Veltri,
brain-derived neurotrophic factor in treatment-resistant depressed patients
receiving electroconvulsive therapy. Eur. Neuropsychopharmacol., 19,
73. Evans, D.L., Pedersen, C.A. and Tancer, M.E. (1987) ECT in the treatment
of organic psychosis in Huntington’s disease. Convuls. Ther., 3, 145–150.
74. Ranen, N.G., Peyser, C.E. and Folstein, S.E. (1994) ECT as a treatment for
depression in Huntington’s disease. J. Neuropsychiatry Clin. Neurosci., 6,
75. Druss, B. and Pincus, H. (2000) Suicidal ideation and suicide attempts in
general medical illnesses. Arch. Intern. Med., 160, 1522–1526.
76. Farrer, L.A. (1986) Suicide and attempted suicide in Huntington disease:
implications for preclinical testing of persons at risk. Am. J. Med. Genet.,
77. Martin, B., Ji, S., Maudsley, S. and Mattson, M.P. (2010) ‘Control’
laboratory rodents are metabolically morbid: why it matters. Proc. Natl
Acad. Sci. USA, 107, 6127–6133.
78. Barichello, T., Bonatto, F., Feier, G., Martins, M.R., Moreira, J.C.,
Dal-Pizzol, F., Izquierdo, I. and Quevedo, J. (2004) No evidence for
oxidative damage in the hippocampus after acute and chronic electroshock
in rats. Brain Res., 1014, 177–183.
79. Ferrante, R.J., Andreassen, O.A., Jenkins, B.G., Dedeoglu, A.,
Kuemmerle, S., Kubilus, J.K., Kaddurah-Daouk, R., Hersch, S.M. and
Beal, M.F. (2000) Neuroprotective effects of creatine in a transgenic
mouse model of Huntington’s disease. J. Neurosci., 20, 4389–4397.
80. Schmued, L.C., Stowers, C.C., Scallet, A.C. and Xu, L. (2005)
Fluoro-Jade C results in ultra high resolution and contrast labeling of
degenerating neurons. Brain Res., 1035, 24–31.
Human Molecular Genetics, 2011, Vol. 20, No. 4 669