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Inducing a long-term potentiation in the dentate gyrus is sufficient to produce rapid antidepressant-like effects

Molecular Psychiatry volume 23, pages 587–596 (2018)Cite this article

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Abstract

Recent hypotheses propose that one prerequisite to obtain a rapid antidepressant (AD) effect would reside in processes of synaptic reinforcement occurring within the dentate gyrus (DG) of the hippocampus independently from neurogenesis. However, to date no relationship has been established between an increased DG synaptic plasticity, and rapid AD-like action. To the best of our knowledge, this study shows for the first time that inducing a long-term potentiation (LTP) within the DG by stimulating the perforant pathway (PP) is sufficient to induce such effects. Thus, Sprague-Dawley rats having undergone a successful LTP displayed a significant reduction of immobility when passed acutely 3 days thereafter in the forced swimming test (FST). Further, in a longitudinal paradigm using the pseudo-depressed Wistar-Kyoto rat strain, LTP elicited a decrease of FST immobility after only 2 days, whereas the AD desipramine was not effective before 16 days. In both models, the influence of LTP was transient, as it was no more observed after 8–9 days. No effects were observed on the locomotor activity or on anxiety-related behavior. Theta-burst stimulation of a brain region anatomically adjacent to the PP remained ineffective in the FST. Immunoreactivity of DG cells for phosphorylated histone H3 and doublecortin were not modified three days after LTP, indicating a lack of effect on both cell proliferation and neurogenesis. Finally, depleting brain serotonin contents reduced the success rate of LTP but did not affect its subsequent AD-like effects. These results confirm the ‘plastic DG’ theory of rapid AD efficacy. Beyond, they point out stimulations of the entorhinal cortex, from which the PP originates, as putative new approaches in AD research.

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Acknowledgements

This study was funded by grants from the Agence Nationale de la Recherche (ANR Spade 2009-MNPS-026.01 and MemoNeuro 2010-BLAN-1408.01), as well as by financial supports from the INSERM, the Bordeaux and Lyon 1 Universities, and the Région Aquitaine.

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  1. A Kanzari and C Bourcier-Lucas: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM and Université Claude Bernard Lyon 1, Institut Cellule Souche et Cerveau U846, Lyon, France

    A Kanzari, A Freyssin, N Haddjeri & G Lucas

  2. Department of Biology, Université de Tunis El Manar, Tunis, Tunisia

    A Kanzari

  3. INSERM and Université de Bordeaux, Neurocentre Magendie U1215, Bordeaux, France

    C Bourcier-Lucas, D N Abrous & G Lucas

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  1. A Kanzari
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Correspondence to G Lucas.

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Kanzari, A., Bourcier-Lucas, C., Freyssin, A. et al. Inducing a long-term potentiation in the dentate gyrus is sufficient to produce rapid antidepressant-like effects. Mol Psychiatry 23, 587–596 (2018). https://doi.org/10.1038/mp.2017.94

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