2026 ECNP Congress

PS03-3122

Hippocampal transcriptomic profiling after electroconvulsive stimulation in adolescent male and female rats

Ruben Garcia-Cabrerizo — M.J. Garcia-Fuster · University of the Balearic Islands, Research Institute of Health Sciences- IUNICS, Palma, Spain

2026 ECNP Congress

Adolescent depression remains a major clinical challenge, because conventional pharmacological approaches often show delayed onset, limited efficacy and marked sex-related variability during this developmental period. Electroconvulsive therapy is one of the most effective fast-acting interventions for treatment-resistant depression and its preclinical correlate, electroconvulsive stimulation (ECS), provides a useful strategy to investigate age- and sex-dependent mechanisms of antidepressant efficacy. Our previous work showed that repeated ECS, induced antidepressant-like effects in adolescent males, whereas adolescent females were largely insensitive or even showed detrimental behavioral responses under the same conditions [1]. Subsequent studies indicated that ECS regulates hippocampal neurogenesis and plasticity-related markers in both sexes [1,2] and that efficacy in females may depend on stimulation intensity and/or sex-steroid tone, since reducing current intensity in adult females or blocking aromatase during adolescence improved the behavioral response [3,4]. Based on this context, the present study used a transcriptomic approach to explore whether the sex-dependent behavioral effects of adolescent ECS are associated with differential hippocampal gene-expression signatures. A total of 27 Sprague-Dawley rats were handled on postnatal days (PND) 43-44 and exposed during mid-adolescence to either SHAM (7 male-SHAM and 6 female-SHAM) or repeated ECS (95 mA, 0.6 s, 100 Hz; 1 session/day for 5 consecutive days, PND 46-50) (7 male-ECS and 7 female-ECS). Animals were sacrificed 24 h after the last ECS session (PND 51) and hippocampal samples were collected for transcriptomic profiling. This time point was selected to capture early molecular adaptations induced by repeated ECS before the emergence of more delayed downstream plasticity-related responses. Exploratory transcriptomic profiling revealed a clear separation between ECS- and SHAM-treated animals, supporting a robust hippocampal molecular response to repeated ECS. Differential expression analysis identified 114 genes out of 23,188 analyzed transcripts (0.49%) meeting the predefined filtering criteria (absolute fold-change >1.5 and nominal p<0.05) with 73 genes upregulated and 41 downregulated after ECS. This ECS responsive profile included genes related to neuropeptide signaling, neurotrophic regulation, plasticity-associated processes, extracellular matrix remodeling and activity-dependent transcriptional responses, suggesting that repeated ECS rapidly engages multiple hippocampal pathways involved in neuronal adaptation and antidepressant-like mechanisms. In contrast, when ECS-treated males and females were compared directly, sex-related differences were mainly driven by sex chromosome-linked transcripts, rather than by a broad hippocampal transcriptional program selectively associated with the behavioral lack of efficacy previously observed in female rats. Thus, although ECS produced a marked hippocampal transcriptomic response, this early molecular profile did not reveal a strong sex-specific ECS-induced signature beyond expected chromosomal sex differences. Overall, these preliminary findings indicate that repeated ECS induces a robust hippocampal transcriptional response during adolescence, but this response does not appear to explain the male-specific antidepressant-like efficacy previously observed at this post-treatment time point. Ongoing pathway-level analyses will determine whether more subtle functional networks, rather than individual genes, contribute to the sex-dependent antidepressant-like effects of ECS during adolescence.

References

  1. García-Cabrerizo R, Ledesma-Corvi S, Bis-Humbert C, García-Fuster MJ. Sex differences in the antidepressant-like potential of repeated electroconvulsive seizures in adolescent and adult rats: Regulation of the early stages of hippocampal neurogenesis. Eur Neuropsychopharmacol. 2020;41:132-145.
  2. Ledesma-Corvi S, García-Fuster MJ. Electroconvulsive seizures regulate various stages of hippocampal cell genesis and mBDNF at different times after treatment in adolescent and adult rats of both sexes. Front Mol Neurosci. 2023;16:1275783.
  3. Ledesma-Corvi S, García-Fuster MJ. Comparing the antidepressant-like effects of electroconvulsive seizures in adolescent and adult female rats: an intensity dose-response study. Biol Sex Differ. 2023;14(1):67.
  4. Ledesma-Corvi S, García-Fuster MJ. Aromatase Inhibition and Electroconvulsive Seizures in Adolescent Rats: Antidepressant and Long-Term Cognitive Sex Differences. Int J Neuropsychopharmacol. 2023;26(9):607-615.