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Electroconvulsive Stimulation in Rats Induces Alterations in the Hippocampal miRNome: Translational Implications for Depression

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Abstract

MicroRNAs (miRNAs) may contribute to the development of depression and its treatment. Here, we used the hypothesis-neutral approach of next-generation sequencing (NGS) to gain comprehensive understanding of the effects of a course of electroconvulsive stimulation (ECS), the animal model equivalent of electroconvulsive therapy (ECT), on rat hippocampal miRNAs. Significant differential expression (p < 0.001) of six hippocampal miRNAs was noted following NGS, after correcting for multiple comparisons. Three of these miRNAs were upregulated (miR-132, miR-212, miR-331) and three downregulated (miR-204, miR-483, miR-301a). qRT-PCR confirmed significant changes in four of the six miRNAs (miR-132, miR-212, miR-204, miR-483). miR-483 was also significantly reduced in frontal cortex, though no other significant alterations were noted in frontal cortex, cerebellum, or whole blood. Assessing the translatability of the results, miR-132 and miR-483 were significantly reduced in whole blood samples from medicated patients with depression (n = 50) compared to healthy controls (n = 45), though ECT had no impact on miRNA levels. Notably, pre-ECT miR-204 levels moderately positively correlated with depression severity at baseline and moderately negatively correlated with mood score reduction post-ECT. miRNAs were also examined in cerebrospinal fluid and serum from a separate cohort of patients (n = 8) treated with ECT; no significant changes were noted post-treatment. However, there was a large positive correlation between changes in miR-212 and mood score post-ECT in serum. Though replication studies using larger sample sizes are required, alterations in miRNA expression may be informative about the mechanism of action of ECS/ECT and in turn might give insight into the neurobiology of depression.

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Data Availability

The datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank the patients and healthy volunteers who participated in this study.

Funding

This work was supported by a NARSAD Young Investigator Grant 2014 from the Brain and Behavior Research Foundation awarded to KR (22516) and an award from the Health Research Board (HRB), Ireland (TRA/2007/5&HPF/2010/17).

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Authors and Affiliations

  1. Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland

    Karen M. Ryan & Declan M. McLoughlin

  2. Department of Psychiatry, Trinity College Dublin, St Patrick’s University Hospital, Dublin 8, Ireland

    Karen M. Ryan & Declan M. McLoughlin

  3. Department of Histopathology, Trinity Translational Medicine Institute, Trinity College Dublin, St. James’s Hospital, Dublin, Ireland

    Paul Smyth, Gordon Blackshields & Orla Sheils

  4. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty, Mannheim/Heidelberg University, Mannheim, Germany

    Laura Kranaster & Alexander Sartorius

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  1. Karen M. Ryan
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  7. Declan M. McLoughlin
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Contributions

KR, GB, PS, OS, and DM conceptualised and designed the study. KR, PM, and GB were involved in the acquisition and analysis of the data. LK and AS provided CSF and serum samples. KR and DM interpreted the data and drafted the manuscript. All authors critically reviewed the manuscript and approved its publication.

Corresponding author

Correspondence to Karen M. Ryan.

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Ethics Approval

Experimental procedures with animals were approved by the Bioresources Ethics Committee, Trinity College Dublin and were in compliance with the European Council Directive (86/609/EEC). Ethical approval for the human portion of this study was granted by the St Patrick’s University Hospital Research Ethics Committee in Dublin (Protocol No. 012/07) and the local ethics committee in Mannheim, Germany. The human studies were performed in accordance with the Declaration of Helsinki.

Consent to Participate

Written informed consent was obtained from all individual participants included in the study.

Consent for Publication

Not applicable.

Competing Interests

DMM has received speaker’s honoraria from MECTA and Otsuka and an honorarium from Janssen for participating in an esketamine advisory board meeting. KR, LK, AS, PS, GB, and OS have no competing interests to declare.

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Ryan, K.M., Smyth, P., Blackshields, G. et al. Electroconvulsive Stimulation in Rats Induces Alterations in the Hippocampal miRNome: Translational Implications for Depression. Mol Neurobiol 60, 1150–1163 (2023). https://doi.org/10.1007/s12035-022-03131-8

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