Comparing the antidepressant-like effects of electroconvulsive seizures in adolescent and adult female rats: an intensity dose–response study

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 indicative 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 survival 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 antidepressant-like effects induced by ECS.

Electroconvulsive seizures regulate various stages of hippocampal cell genesis and mBDNF at different times after treatment in adolescent and adult rats of both sexes

“…In line with prior results demonstrating that ECS increased hippocampal cell genesis in adult male rats (reviewed by An and Wang, 2022 ), and together with our prior data that proved increases in cell proliferation and neuronal progenitors in adolescent rats of both sexes and adult male rats ( García-Cabrerizo et al, 2020 ; Ledesma-Corvi and García-Fuster, 2023 ), the present results provide new data on the long-term survival of cells of different ages at the time of analysis (age range of BrdU +cells:12-43 days) and labeled by BrdU prior to treatment. Note that the absolute number of +cells cannot be directly compared between both sexes, ages and/or days post-treatment, since brains were collected at different experimental waves with particular environmental conditions (e.g., García-Cabrerizo and García-Fuster, 2016 ).…”

“…In the present case, one of the compensatory adaptative mechanisms taking place could for example be mediating the inactivation of neural stem cells in response to particular stimuli (e.g., Matsubara et al, 2021 ). As for neurogenic differentiation, ECS treatment induced significant increases in the number of NeuroD +cells as detected 1- and 8-days post-treatment during adolescence ( Supplementary Figure S1 ; García-Cabrerizo et al, 2020 ; Ledesma-Corvi and García-Fuster, 2023 ); while in adulthood increased NeuroD was found up to 15-days post-treatment, with a peak expression observed 8-days post-treatment, to then normalize at 30 days ( Supplementary Figure S1 ).…”

“…In this context, animals were handled by the experimenter prior to any procedures to reduce future stress and/or suffering. Moreover, in terms of reducing and reusing animals, some of these rats were previously used to behaviorally characterize the differences in the antidepressant-like responses induced by ECS in male and female rats, both during adolescence and adulthood (see García-Cabrerizo et al, 2020 ; Ledesma-Corvi and García-Fuster, 2023 ).…”

“…This analysis was done for male and female adolescent and adult rats. Moreover, Ki-67 (an intrinsic marker of cell proliferation) and NeuroD (which labels neurogenic differentiation; Figure 1A ) were assessed exclusively in adult female rats, since their regulation in adolescent rats of both sexes as well as in adult males was previously performed (see García-Cabrerizo et al, 2020 ; Ledesma-Corvi and García-Fuster, 2023 ). These markers have been previously reliably used to label how a particular treatment might affect the different stages of hippocampal neurogenesis by immunohistochemistry (for further details on marker selection see García-Fuster et al, 2010 ).…”

“…Also, all prior studies were almost exclusively done in adult male rodents, with little to inexistent data for adolescence (e.g., Jonckheere et al, 2018 ; An and Wang, 2022 ). In this regard, we have performed two recent studies proving that repeated ECS increased cell proliferation and/or vastly boosted young neuronal survival in a course manner and in a similar way for both sexes and independently of age ( García-Cabrerizo et al, 2020 ; Ledesma-Corvi and García-Fuster, 2023 ).…”