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Ledesma‑Corviand García‑Fuster
Biology of Sex Dierences (2023) 14:67
https://doi.org/10.1186/s13293‑023‑00552‑5
RESEARCH
Comparing theantidepressant‑like eects
ofelectroconvulsive seizures inadolescent
andadult female rats: anintensity dose–
response study
Sandra Ledesma‑Corvi1,2 and M. Julia García‑Fuster1,2,3*
Abstract
Background The induction of electroconvulsive seizures (ECS) in rodents induces sex‑ and age‑specific disparities
in antidepressant‑like responses, with females and young age being the most unresponsive ones. Since the electrical
charge needed to induce an effective convulsion is also altered by these variables, our aim was to compare different
dose‑intensities of ECS exclusively in female rats, since there is a lack of preclinical data characterizing this particular
sex, while also evaluating efficacy during distinctive age periods of treatment (adolescence vs. adulthood).
Methods Adolescent and adult female Sprague–Dawley rats were exposed to an intensity dose–response study
(55, 75 or 95 mA; 0.6 s, 100 Hz, 1 session/day, 5 days). The particular characteristics of the induced convulsions
(tonic, clonic, recovery times) were monitored during treatment. Antidepressant‑like responses were evaluated
under the stress of the forced‑swim test 1‑, 3‑, and 7‑days post‑treatment (i.e., improved immobility time as an indica‑
tive of an antidepressant‑like response), and brains were collected 24 h later (8 days post‑treatment) to evaluate
potential changes in hippocampal neurogenesis (Ki‑67 and NeuroD) by immunohistochemistry.
Results The lowest intensities tested of ECS (55 and 75 mA) induced an antidepressant‑like effect in adult female
rats, but rendered insufficient in adolescence. The lack of efficacy observed in adolescent rats paralleled differences
in the characteristics of the seizures induced by ECS as compared to adulthood. In line with prior results, different
dose‑intensities of ECS modulated hippocampal neurogenesis in a comparable fashion with age (i.e., increased sur‑
vival of neural progenitors 8 days post‑treatment).
Conclusions In conjunction, these results reinforce the importance of fine‑tuning the parameters of ECS that might
render efficacious while considering sex and age as essential variables for treatment response, and suggest that other
molecular mechanisms, beside the partial role of hippocampal neurogenesis, might be participating in the antide‑
pressant‑like effects induced by ECS.
Highlights
• There are clear sex and age differences in the antidepressant‑like effects of ECS.
Open Access
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Biology of Sex Differences
*Correspondence:
M. Julia García‑Fuster
j.garcia@uib.es
Full list of author information is available at the end of the article
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Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
Background
Electroconvulsive therapy (ECT) is a well-established
treatment option for adult patients with treatment-
resistant depression (e.g., [1, 2]), which is defined as the
failure to respond to at least two different antidepres-
sant treatments within a certain time and that affects
around 20–30% of patients with major depressive dis-
orders (MDD) (e.g., [3, 4]). However, the use of ECT in
child and adolescent populations is less common and
remains frequently unavailable, even though up to 60% of
these young patients do not respond satisfactorily to first-
line treatments (e.g., [5]) and despite the fact that ECT
is generally considered safe at early ages (as detailed in
the book edited by [6]). In an attempt to provide novel
treatment strategies for adolescents with MDD, a recent
systematic review [7] concluded that ECT was safe and
effective for the treatment of mood disorders in child and
adolescent populations. In conjunction with other recent
reports that also described and/or revised the outcome of
ECT in adolescents with MDD (e.g., [8–12]), the general
recommendation from all of them would be that ECT
should be considered and more broadly use in severe and
treatment-refractory cases for adolescence.
e efficacy, safety and applicability of current ECT prac-
tices are the result of a series of improvements in treatment
delivery, which have focused on preserving and improving
efficacy (e.g., by adjusting ECT electrical dose, stimulus
parameters and/or electrode placement), while minimizing
the potential cognitive side effects (e.g., [13, 14]). Moreo-
ver, these parameters have to be adjusted by age and sex,
since previous studies reported variations in the electrical
charge needed to induce an effective convulsion (e.g.,
[15–19]): for example, women seem to require less charge
than men of the same age to induce an optimal seizure, and
for both sexes the charge needs to be increased with age
(e.g., [20]). Interestingly, these differences can be modeled
in experimental rodents through the induction of electro-
convulsive seizures (ECS). In fact, a recent study from our
group demonstrated age- and sex-specific differences in
the antidepressant-like potential of repeated ECS (95mA
for 0.6s at a frequency of 100Hz square wave pulses, pulse
width 0.6ms, 5days, 1 shock/day), since it worked when
administered during adolescence or adulthood in male rats
(although with a shorter length in adolescence as compared
to adulthood), while in females rendered deleterious dur-
ing adolescence (naïve rats) and ineffective in adulthood
(maternally deprived rats; see [21]). Against this back-
ground the present follow-up study aimed at evaluating
alternative dosing parameters (dose intensity study: 55, 75
and 95mA) that could potentially induce an effective-like
response in female rats, while comparing their response by
age (adolescence vs. adulthood). Moreover, the next step
evaluated the regulation of cell markers involved in the
early stages of hippocampal neurogenesis (i.e., cell prolif-
eration and early neuronal survival) as a potential mecha-
nism behind the effects induced by ECS in female rats (e.g.,
[21]).
Methods
Animals
In this study we utilized exclusively female Sprague–
Dawley rats (31 adolescents and 60 adults; Fig. 1) bred
• Low dose intensities of ECS exerted antidepressant‑like effects in adult female rats.
• ECS, at the doses tested, did not induce behavioral changes in adolescent female rats.
• ECS increased neurogenesis independently of the dose and age of treatment.
Keywords ECT, Sex, Antidepressant, Neurogenesis, Hippocampus, Age
Plain Language Summary
Although the induction of electroconvulsive seizures (ECS) is a safe therapeutical option for treatment‑resistant
depression, there are important differences in treatment response driven by biological sex and age that require
further characterization for ensuring optimal outcomes. In fact, most of the preclinical literature is centered in adult
male rodents, with almost no prior studies characterizing ECS’ response in adolescent female rodents. In this con‑
text, the present study compared the antidepressant‑like responses induced by different intensity doses of ECS
(55, 75 or 95 mA; 0.6 s, 100 Hz, 1 session/day, 5 days), exclusively in female rats (adolescent and adult). The results
showed that the lowest doses tested (55 or 75 mA) induced an antidepressant‑like response in adult female rats,
while no dose was capable of inducing efficacy in adolescent female rats. These results replicated prior data from our
group showing the inefficacy of the 95‑mA dose at both ages, while demonstrating that lowering the dose is suf‑
ficient to exert efficacy in female adult rats. Further studies should center in adjusting the parameters to elicit efficacy
in females during adolescence.
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Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
in the animal facility at the University of the Balearic
Islands. Rats were housed in the vivarium (22°C, 70%
humidity, 12:12h light/dark cycle, lights on at 8:00 h
and off at 20:00h) in standard cages with 2–4 animals
with continuous access to a standard diet and tap water.
All procedures were performed following the ARRIVE
guidelines [22] and the EU Directive 2010/63/EU of the
European Parliament and of the Council after approval
by the Local Bioethical Committee (University of the
Balearic Islands) and the regional Government (Conselle-
ria Medi Ambient, Agricultura i Pesca, Direcció General
Agricultura i Ramaderia, Govern de les Illes Balears). e
specific stages of the estrous cycle were not monitored
during the experimental procedures since the cyclicity
of females was not part of our research question (see [23,
24]), but also because female rodents are not more vari-
able than male rodents (e.g., [25]) and their spontaneous
behavior might reflect individual variation rather than
estrous state (see recent article by [26]).
Electroconvulsive seizures (ECS)
Female rats from each age group (adolescence, postna-
tal days, PND 46–50, Fig. 1a; adulthood, PND 95–99,
Fig.1b) were exposed to a total of 5 shocks (1 per day
during the light period: between 10:00 and 12:00h) using
a pulse generator (ECT Unit 7801; Ugo Basile, Italy)
at different intensities (groups of 55, 75 or 95mA) for
0.6s at a frequency of 100Hz square wave pulses and a
pulse width of 0.6ms, through earclip electrodes during
independent experimental studies. While the intensity
of 95mA was selected from our own prior studies [21,
27], the lower intensities of 55 and 75mA were based
on other studies (e.g., [28–30]). All control rats were
connected to the electrodes with no electrical current
(SHAM groups; Fig.1). e lengths (s) of the tonic and
clonic seizure activities, as well as the recovery time were
monitored on days 2, 3 and 4 of treatment by an experi-
menter blind to the treatment groups (see Fig.1). Each
time was calculated from the end of the prior phase, not
as an overall time from ECS exposure. To estimate the
mean time adolescent or adult female rats spent in each
phase, we calculated an average value for days 2, 3 and 4
and treatment for each rat, which was utilized to calcu-
late the mean overall value.
Forced‑swim test
Rats were screened in the forced-swim test to obtain their
basal immobility rates (e.g., [21]). To do so, all rats were
individual placed in water tanks (41 cm high × 32 cm
diameter, 25cm depth; temperature of 25 ± 1 °C) dur-
ing 15min (pre-test session; PND 42 or PND 91). e
next day, rats were forced again to swim for a 5-min test
session that was videotaped. Immobility rates were cal-
culated for each rat (Behavioral Tracker software, CA,
USA) and used to allocate rats in separate experimental
groups that were counterbalanced by immobility (see
Fig.1). Since this test has been the goal standard screen-
ing tool in the industry for antidepressant-like responses
(e.g., [31]), and is still widely used for screening novel
potential antidepressants (e.g., [32]), later on, the behav-
ioral response induced by ECS was evaluated 1-, 3- and
7-days post-treatment by re-exposing rats to 5min ses-
sions in the forced-swim test (as followed in our prior
experimental procedures [21]). is repetitive screening
testing provided reliable measurements of the behavioral
response across time (see [21, 32–35]).
Immunohistochemical analyses
Rats were killed by rapid decapitation 8days post-treat-
ment; note that while all adolescent rats were used for
Fig. 1 Experimental timeline. Effects induced by different intensity doses of ECS (55, 75 or 95 mA for 0.6 s, 100 Hz, 5 days, 1 dose/day vs.
SHAM‑treated rats) in a adolescent or b adult female rats. D, day of post‑treatment; ECS, electroconvulsive seizures; FST, forced‑swim test; PND,
post‑natal day
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Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
this analysis (Fig.1), only a subgroup of adult rats were
collected (SHAM, n = 11; ECS-55 mA, n = 12; ECS -
75mA, n = 11; ECS-95mA, n = 8). e left half-brain was
rapidly frozen in −30°C isopentane and then stored at
−80°C until the whole extent of the hippocampus (-1.72
to -6.80mm from Bregma) was cryostat-cut in 30 µm
serial sections. For each rat, we collected 3 series of 8
slides, with each slide containing 8 tissue-sections, from
the most anterior, middle and most posterior part of the
hippocampus respectively, and as routinely performed
for over 10years (e.g., [21, 36, 37]). Subsequently, we uti-
lized 3 slides (1 from each series, 24 tissue-sections in
total) per marker (Ki-67 for cell proliferation and NeuroD
for neuronal progenitors) in which to perform immu-
nohistochemical analysis in the whole extent of the hip-
pocampus as previously described [21, 36, 37]. Briefly,
tissue was post-fixed in 4% paraformaldehyde to be later
exposed to several steps such as epitope retrieval (only
for Ki-67) and/or incubation with a peroxidase solu-
tion, and blocking in BSA. Later on, tissue was incubated
overnight with the appropriate primary antibody (i.e.,
polyclonal rabbit anti-Ki-67, 1:20,000, kindly provided
by Dr. Huda Akil and Dr. Stanley J. Watson, University
of Michigan, MI, USA; goat anti-NeuroD1, 1:10,000;
R&D Systems, Inc. a Bio-Techne Brand, MN, USA), fol-
lowed by, the next day, a 1-h incubation with 1:1000 of
biotinylated anti-rabbit or anti-goat secondary antibody
(Vector Laboratories, CA, USA). To visualize Ki-67 or
NeuroD + cells, we utilized an Avidin/Biotin complex
(Vectastain Elite ABC kit; Vector Laboratories) and the
chromogen 3,3′-diaminobenzidine (DAB) (with nickel
chloride for NeuroD); when detecting Ki-67 + cells, tissue
was counterstained with cresyl violet. Finally, all tissue
was dehydrated in graded alcohols, immersed in xylene
and cover-slipped with Permount®.
To quantify the number of immunostained positive
cells we first coded the slides so the experimenter was
blind to the experimental groups. en, Ki-67 or Neu-
roD + cells were counted with a 63× objective lens and
10× ocular lens (amplification of 630×) under a Leica
DMR light microscope, and following a modified unbi-
ased protocol [38, 39] that counts every 8th section in the
entire hippocampal dentate gyrus (for further details on
the quantification or the method followed please check
our prior study led by [21]). Finally, the number of Ki-67
or NeuroD + cells obtained for each rat was multiplied
by the sampling factor 8 to provide a final estimate of the
total + cells per marker and rat (see [36, 37]; also see [21]
for further details on the quantification method).
Statistical analysis
Data was analyzed and graphs were plotted with Graph-
Pad Prism, Version 9.5 (GraphPad Software, CA, USA).
Results are displayed as bar graphs incorporating mean
values ± standard errors of the mean (SEM), and sym-
bols for individual values for each rat (e.g., see guidelines
for reporting data and statistical results in experimental
pharmacology; [40, 41]). When comparing the proper-
ties of the convulsions elicited by the different intensi-
ties applied by ECS, we used two-way repeated measures
(RM) ANOVAs with ECS intensity and Day of treatment
as independent variables, or two-way ANOVAs with ECS
intensity and Age as independent variables followed by
Sidak’s post-hoc test when appropriate. One-way ANO-
VAs were used to ensure that there were no basal changes
in the time spent in the different behaviors (immobility,
climbing, swimming) in the forced-swim test prior to
assigning rats to the different experimental groups and
starting ECS treatment. To evaluate the effect induced
by different intensities of ECS treatment across days,
data was analyzed by two-way RM ANOVAs, with Treat-
ment (SHAM, ECS-55mA, ECS-75 mA, ECS-95 mA)
and Day post-treatment used as independent variables.
Finally, changes in Ki-67 and NeuroD + cells were evalu-
ated through one-way ANOVAs. Note that we did not
include age (adolescence vs. adulthood) as an independ-
ent variable because experiments at each age period were
performed at different time points in time, and therefore
brain samples were not collected in parallel. is might
have caused, as we previously described in our hands,
differences in the basal rate of cell genesis among waves
of experimental groups, driven by particular environ-
mental conditions (see [42]). Dunnett’s multiple compar-
isons tests were used to compare each ECS intensity with
the corresponding SHAM group. e level of significance
was set at p ≤ 0.05.
Results
Characteristics oftheseizures induced bydierent
intensities ofECS treatment inadolescent andadult female
rats
All of the different intensities of ECS tested resulted in
a period of tonic–clonic seizure activity, both in ado-
lescent and adult female rats. However, when assessing
the effects of the different intensities utilized for ECS
to elicit the convulsions during adolescence, the results
showed no significant ECS intensity x Day of treatment
interactions for the time rats spent in tonic (F4,38 = 0.56,
p = 0.696, Fig. 2a) or clonic (F4,38 = 1.86, p = 0.137,
Fig.2b) activities, nor in recovery (F4,38 = 0.40, p = 0.805,
Fig.2c). In particular, the average time an adolescent
female rat exposed to ECS (independently of the ECS
intensity or day, and by pooling all rats together) spent
in tonic phase was of 12.3 ± 0.3 s (Fig. 2a), followed
by 12.3 ± 0.3s in clonic seizure activity (Fig. 2b), and
79.6 ± 2.1 s for recovery (Fig. 2c). Similarly, for adult
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Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
female rats there were no changes in the properties
of the convulsions induced by different ECS intensi-
ties across treatment days (tonic: F4,52 = 0.11, p = 0.979,
Fig.2d; clonic: F4,52 = 1.40, p = 0.247, Fig. 2e; recovery:
F4,52 = 1.13, p = 0.354, Fig. 2f). For this age range, how-
ever, the average time an adult female rat exposed to
ECS spent in tonic phase was of 13.5 ± 0.3 s (Fig.2d),
followed by 8.5 ± 0.3s in clonic seizure activity (Fig.2e),
and 36.9 ± 1.3s for recovery (Fig.2f).
If comparing the time adolescent or adult female
rats spent in each phase, two-way ANOVAs, with ECS
intensity and Age as independent variables, found sig-
nificant effects of Age for all variables (tonic: F1,45 = 8.81,
##p = 0.005, Fig. 2g; clonic: F1,45 = 29.42, ###p < 0.001,
Fig. 2h; recovery: F1,45 = 239.5, ###p < 0.001, Fig. 2i), but
only an effect of ECS intensity (F2,45 = 4.14, p = 0.022),
as well as a significant interaction ECS intensity x Age
(F2,45 = 7.91, p = 0.001) for the clonic phase (Fig.2h). Par-
ticularly, Sidak’s multiple comparisons test found that
adult female rats spent significant lower times in the
clonic phase (55 mA: − 3.8 ± 1.2 s, *p = 0.011; 75 mA:
− 6.9 ± 1.1s , ***p < 0.001) as compared to the adolescent
ones (Fig.2h).
Behavioral responses scored underthestress
oftheforced‑swim test followingdierent intensities
ofECS treatment inadolescent andadult female rats
e average times spent in each one of the behaviors
scored in the forced-swim test were similar for adolescent
(immobility: 247.9 ± 4.4 s ; climbing: 36.3 ± 4.0 s; swim-
ming: 14.2 ± 1.4 s) and adult (immobility: 247.4 ± 4.1 s;
climbing: 34.4 ± 4.4 s; swimming: 10.2 ± 0.8 s) rats (see
Fig.3). Rats were allocated in groups by cage and bal-
anced by immobility to generate the treatment groups
as detailed in Fig. 1. One-way ANOVAs did not detect
any significant changes among the rats assigned to each
experimental group for any of the behaviors evaluated
(immobility, climbing or swimming; data not shown in
graphs).
Adolescent ECS exposure modified the time female rats
spent immobile in the forced-swim test (Treatment x Day
interaction: F6,54 = 3.78, p = 0.003). In particular, post-hoc
analysis revealed that ECS increased immobility (i.e.,
indicatives of a prodepressant-like effect) as measured
7days post-treatment (55mA: + 27.5 ± 7.4 s , **p = 0.007;
75 mA: + 27.8 ± 8.0 s , *p = 0.011; 95 mA: + 30.6 ± 6.7 s,
**p = 0.001) vs. SHAM-treated adolescent female rats
Fig. 2 Characteristics of the seizures induced by different intensities of ECS treatment in adolescent and adult female rats. Time spent in tonic (s)
and clonic (s) phases, or in recovery (s) during ECS exposure in (a–c) adolescence and (d–f) adulthood across days 2 and 4 of treatment, or (g–i)
when comparing the average of all days for each phase in adolescence vs. adulthood. Data represents mean ± SEM of the time (s) spent in each
phase. Individual values are shown for each rat (symbols). Two‑way RM ANOVAs did not detect any significant changes in adolescence or adulthood.
Two‑way ANOVAs (independent variables: ECS intensity, Age) followed by Sidak’s multiple comparisons tests: *p < 0.05 and ***p < 0.001 vs. same
intensity‑dose adolescent rats. Significant effects of Age: ##p < 0.01 and ###p < 0.001 when comparing adulthood vs. adolescence
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Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
(Fig.3a). As expected, ECS also altered climbing (Treat-
ment x Day interaction: F6,54 = 3.92, p = 0.003), show-
ing decreased rates 7 days post-treatment (55 mA:
−22.1 ± 6.7s, *p = 0.015; 75mA: − 20.3 ± 7.6s, *p = 0.048;
95 mA: − 22.9 ± 6.5 s, **p = 0.009) vs. SHAM-treated
adolescent female rats (Fig. 3b). Lastly, no Treatment
x Day interaction was observed for swimming behavior
(F6,54 = 2.11, p = 0.067; Fig.3c).
Adult ECS exposure altered the time female rats
spent immobile in the forced-swim test (Treatment x
Day interaction: F6,108 = 9.08, p < 0.001), suggesting an
antidepressant-like effect detected 1 day after treat-
ment, both for the 55 mA (− 31.7 ± 10.7 s, *p = 0.018)
and 75mA (− 49.6 ± 16.2 s, *p = 0.022) intensities and as
compared to SHAM-treated rats (Fig.3d). Besides, rats
exposed to ECS showed increased immobility (i.e., as also
observed in adolescent female rats) 7days post-treatment
(55mA: + 35.8 ± 8.7 s, **p = 0.001; 95 mA: + 44.8 ± 10.9 s,
**p = 0.001) vs. SHAM-treated adult female rats (Fig.3d).
As expected, ECS modulated the time rats spent climb-
ing (Treatment x Day interaction: F6,74 = 3.63, p = 0.003),
and contrarily to what was observed for immobility, the
results showed overall increased climbing rates 1-day
post-treatment and decreased climbing 7 days post-
treatment (55mA: − 36.2 ± 9.9s, **p = 0.005) vs. SHAM-
treated adult female rats (Fig.3e). Finally, no Treatment
x Day interaction was observed for swimming behavior
(F6,74 = 0.81, p = 0.567; Fig.3f).
Neurogenic‑like eects induced bydierent intensities
ofECS treatment inadolescent andadult female rats
ECS exposure (vs. SHAM) decreased Ki-67 + cells as
measured 8days post-treatment in female adolescent rats
(F3,27 = 18.66, p < 0.001; Fig. 4a). In particular, post-hoc
analysis revealed that ECS decreased hippocampal cell
proliferation at all intensities tested (55mA: − 524 ± 94
Ki-67 + cells, ***p < 0.001; 75 mA: -521 ± 91 Ki-67 + cells ,
***p < 0.001; 95 mA: − 612 ± 91 Ki-67 + cells, ***p < 0.001)
vs. SHAM-treated adolescent female rats (Fig.4a). Con-
trarily, no significant effect was detected for adult female
rats (F3,37 = 2.75, p = 0.056; Fig.4b).
Fig. 3 Behaviors scored under the stress of the forced‑swim test following different intensities of ECS treatment in adolescent and adult female rats.
Time spent in immobile (s), climbing (s) or swimming (s) basally (prior to treatment) or after ECS treatment (1‑, 3‑ and 7‑days post‑treatment) in (a–
c) adolescence and (d–f) adulthood in the forced‑swim test. Data represents mean ± SEM of the time (s) spent in each behavior. Individual values
are shown for each rat (symbols). Two‑way RM ANOVAs followed by Dunnett’s multiple comparisons tests: *p < 0.05 and **p < 0.01 vs. SHAM‑treated
rats (S) at the indicated post‑treatment day
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Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
However, when evaluating the effects of ECS exposure
over the survival of neural progenitors (NeuroD + cells),
the results showed similar effects both in adolescent
(F3,27 = 31.53, p < 0.001; Fig. 4c) and adult (F3,38 = 38.97,
p < 0.001; Fig. 4d) female rats. For adolescent rats, post-
hoc analysis revealed that ECS increased the number
of hippocampal NeuroD + cells at all intensities tested
(55 mA: + 14,233 ± 1758 NeuroD + cells, ***p < 0.001;
75 mA: + 13,584 ± 1698 NeuroD + cells, ***p < 0.001;
95 mA: + 12,809 ± 1698 NeuroD + cells, ***p < 0.001) vs.
SHAM-treated adolescent female rats (Fig. 4c). Simi-
larly, but with a higher magnitude of change, post-hoc
analysis revealed that ECS increased the number of
hippocampal NeuroD + cells at all intensities tested
(55 mA: + 24,727 ± 2763 NeuroD + cells, ***p < 0.001;
75 mA: + 23,497 ± 2823 NeuroD + cells, ***p < 0.001;
95 mA: + 27,297 ± 3076 NeuroD + cells, ***p < 0.001) vs.
SHAM-treated adult female rats (Fig.4d).
Discussion
e present study demonstrated that lowering the
intensity of the pulse applied during ECS induced an
antidepressant-like effect in female adult rats. However,
adolescent female rats showed a decreased sensitivity
to ECS as compared to adulthood since no beneficial
response was observed at any intensity dose tested. ese
age disparities paralleled some changes detected in the
features of the seizures induced by ECS, with adult female
rats showing longer tonic and shorter clonic phases, and
a much quicker recovery time (almost two-fold) as com-
pared to adolescent female rats. At the neurochemical
level some age-particularities were also observed; ECS
decreased hippocampal cell proliferation (Ki-67 + cells)
in adolescent but not in adult female rats as measured
8days post-treatment, but for both ages, there was a vast
increase in young neuronal survival (NeuroD + cells) by
all ECS doses tested. ese results reinforce the impor-
tance of fine-tuning the parameters of ECS that might
render efficacious while considering sex and age as essen-
tial variables for treatment response.
During adolescence, ECS did not induce any improve-
ments in female rats as measured in the forced-swim
test 1- and 3-days post-treatment. In fact, ECS increased
immobility 7days post-treatment for all doses tested, in
line with our previous data [21] and with the negative
impact and/or loss of efficacy described for antidepres-
sants in adolescence (e.g., [43, 44]). Interestingly, ECS
was capable of inducing an antidepressant-like effect in
female adult rats both following 55 or 75mA, suggest-
ing in line with prior literature, that lower intensities
(as opposed to the ineffective dose of 95mA in females,
but effective in males; see [21]) are needed in females
Fig. 4 Neurogenic‑like effects induced by different intensities of ECS treatment in adolescent and adult female rats. Quantitative analysis of a,
b Ki‑67 and c, d NeuroD + cells in the left dentate gyrus of adolescent or adult female rats. Data represents mean ± SEM of the number of + cells.
Individual values are shown for each rat (symbols). The quantification was done in every 8th section through the entire extent of the hippocampal
dentate gyrus and multiplied by the sampling factor 8 to provide an estimation of the total number of + cells per marker. One‑way ANOVAs
followed by Dunnett’s multiple comparisons tests: ***p < 0.001 vs. SHAM (S). Representative images for each treatment group showing Ki‑67 (brown
labeling in the blue granular layer) and NeuroD (dark blue labeling in the blue granular layer) + cells acquired with a light microscope (40× objective
lens) connected to a digital camera
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Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
to observe a therapeutical response (e.g., [20]). Simi-
larly, to what was observed for adolescent rats, the rates
of immobility increased in the ECS groups as measured
7days post-treatment. In conjunction, these data align
with the differences in response to certain antidepres-
sants’ efficacy previously reported for males and females
[21, 32, 45–47], as well as with prior data reporting that
antidepressants differ in efficacy depending on the age
of exposure, being adolescence a less responsive period
than adulthood (e.g., [21, 35, 43]). e lack of a beneficial
effect in adolescence could be attributed to an excessive
ECS intensity for such young animals, which might be
causing the observed negative effects, in line with previ-
ous studies reporting that the electrical charge for effec-
tive responses in young females should be lower than
the one used for older animals [15–20]. Interestingly, a
recent study from our group showed that these young
unresponsive female rats, when pretreated with letrozole
(an aromatase inhibitor that reduces the biosynthesis of
estrogens), displayed improved outcomes for ECS (the
95-mA dose) in terms of inducing an antidepressant-
like response in female adolescent rats, suggesting that,
besides the dose-intensity used, sex hormones also play a
crucial role in the efficacy of the response [48]. erefore,
future studies should evaluate how modulating the dose
intensities used relate to how changes in sex hormones
affect the antidepressant-like response of ECS. All this
information would be key when translating the knowl-
edge acquired into future treatment guidelines to per-
sonalize and/or adjust the dose and regimen of ECS to be
administered for each sex and age.
In fact, very little evidence is documented in clinical
studies that correlated ECT effectiveness and seizure
duration; while changes in seizure duration have been
measured as a potential marker for ECT treatment effi-
cacy (e.g., [49]), these changes did not appear to be asso-
ciated with the antidepressant properties of treatment
(e.g., [50, 51]). In this context, the present data showed
that the 3 intensities tested (55, 75 or 95mA) did not
induce changes in the characteristics of the seizures
induced (tonic and clonic phases, recovery time) by the
ECS daily dose in adolescent or adult female rats. How-
ever, when comparing the results by age, adult female rats
showed different characteristics of the seizures induced
as compared to adolescent rats: slightly longer tonic
phase, paired with a shorter clonic phase, and a faster
recovery time (almost two-fold quicker) in adulthood.
Interestingly, the lowest dose-intensities tested (55 and
75mA), that also induced an antidepressant-like effect
in adult female rats, showed significantly lower clonic
times than adolescent rats, suggesting a possible role for
the type of seizure induced in the age-related behavio-
ral responses. us, future experiments will center in
evaluating alternative dosing parameters for the electrical
charge and seizure threshold that could potentially ren-
der effective in female adolescent rats.
Given the age-specific differences in the antidepres-
sant-like responses induced by different dose-intensities
of ECS in female rats, we then evaluated the early stages
of hippocampal neurogenesis (i.e., cell proliferation and
neural progenitors) as a possible mechanism behind these
age-disparities. In particular, the rate of cell proliferation
was decreased in female adolescent rats treated with all
dose-intensities of ECS, and as measured 8 days post-
treatment, but not in adult rats. ese results align with
our previous findings showing that repeated ECS (dose
intensity of 95mA) induced an early increase in cell pro-
liferation (observed 1day post-treatment) that later led
to a decrease in the number of Ki-67 + cells, as observed
8days post-treatment in adolescent male or female rats,
or 15days post-treatment in adult male rats (see [21]),
while describing similar magnitude results (not dose-
related) in female rats treated with other ECS intensities
(55 and 75mA). erefore, the decrease observed post-
treatment could be the result of an adaptive time-course
mechanism following an initial excessive increase, and/
or, as previously discussed (see [21]), the consequence of
a series of stressful forced-swim tests leading to a drop
in cell proliferation, since stress impairs hippocampal
neurogenesis. Moreover, ECS (also independently of the
intensity applied) increased hippocampal neural progeni-
tors as labeled by NeuroD + cells, and measured 8 days
post-treatment, in female adolescent and adult rats. As
discussed in more detail in our prior publication (see
[21]), although this excitatory pro-neurogenic activity is
traditionally considered beneficial, one could not exclude
the possibility that seizures might generate misplaced
neurons with irregular morphological and electrophysi-
ological features, such as the ones observed in epileptic
rodent models, a process described as aberrant neuro-
genesis (e.g., [52, 53]), and whose functions stills need to
be defined. In fact, since newly generated proliferating
cell and neural progenitors were only partially needed for
ECS’ antidepressant-like response to occur (see [21]), the
changes induced by ECS might contribute to other roles
in the hippocampus (see [54]), such as promoting struc-
tural plasticity (e.g., reviewed by [55]), gliogenesis [56],
synaptogenesis (e.g., [57]) and angiogenesis [58], that
might even be mediating some of the long-term conse-
quence induced by ECS (e.g., [14]), and that deserve fur-
ther characterization. Overall, the present data, together
with our prior study [21], report that different dose-
intensities of ECS modulated hippocampal neurogenesis
in a comparable fashion with age (i.e., decreased cell pro-
liferation observed 8days post-treatment for adolescent
rats, and expected 15 days post-treatment for adults;
Page 9 of 11
Ledesma‑Corviand García‑Fuster Biology of Sex Dierences (2023) 14:67
increased survival of neural progenitors 8 days post-
treatment). erefore, since ECS only rendered effica-
cious in adult female rats, but neurogenesis was regulated
similarly for both ages, the observed antidepressant-like
response in adulthood might be in part driven by other
molecular mechanisms (e.g., monoaminergic transmis-
sion, e.g., [59]; neurotrophic changes, e.g., [60, 61]) in
hippocampus or other brain regions (e.g., see recent
reviews by [62, 63]).
Perspectives andsignicance
ese results proved that decreasing the intensity of the
pulse applied during ECS rendered effective by induc-
ing an antidepressant-like effect in adult female rats,
but was insufficient in adolescence. e lack of efficacy
observed in adolescence might be explained by differ-
ences in the characteristics of the seizures induced by
ECS as compared to adulthood. Moreover, the early neu-
rogenic-like capabilities induced by ECS, observed both
in adolescence and adulthood, go beyond the regulation
of its antidepressant-like effects and deserves a broaden
characterization. e present data reinforce the need
of fine-tuning the parameters of ECS to render efficacy
when considering sex and age as essential variables for
treatment response.
Acknowledgements
The authors would like to thank Laura Gálvez‑Melero who helped with
procedural assistance and Drs. Huda Akil and Stanley J. Watson (University of
Michigan, Ann Arbor, MI, USA) for kindly providing Ki‑67 antibody.
Author contributions
SL‑C and MJG‑F were responsible for the study concept and design. SL‑C
conducted the experiments and analyzed the behavioral and molecular data.
MJG‑F wrote the first draft of the manuscript. Both authors contributed to and
have approved the final version of the manuscript.
Funding
Research was funded by PID2020‑118582RB‑I00 (MCIN/AEI/10.
13039/501100011033); PDR2020/14 (Comunitat Autònoma de les Illes Balears
through the Direcció General de Política Universitària i Recerca with funds
from the Tourist Stay Tax Law ITS 2017‑006) to MJG‑F. The program JUNIOR
(IdISBa, GOIB) supported SL‑C’s salary.
Availability of data and materials
The datasets used and/or analyzed during the current study can be made
available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Experimental procedures were conducted according to the ethical guidelines
for the care and use of laboratory animals. Experiments were approved by the
local animal care committee (CEEA).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 IUNICS, University of the Balearic Islands, Cra. de Valldemossa Km 7.5,
07122 Palma, Spain. 2 Health Research Institute of the Balearic Islands (IdISBa),
Palma, Spain. 3 Department of Medicine, University of the Balearic Islands,
Palma, Spain.
Received: 10 July 2023 Accepted: 22 September 2023
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