Abstract
When administered as a single subanesthetic dose, the n-methyl-d-aspartate (NMDA) receptor antagonist, ketamine, produces rapid (within hours) and relatively sustained antidepressant actions even in treatment-resistant patients. Preclinical studies have shown that ketamine increases dendritic spine density and synaptic proteins in brain areas critical for the actions of antidepressants, yet the temporal relationship between structural changes and the onset of antidepressant action remains poorly understood. In this study, we examined the effects of a single dose of S-ketamine (15 mg/kg) on dendritic length, dendritic arborization, spine density, and spine morphology in the Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rat model of depression. We found that already 1 h after injection with ketamine, apical dendritic spine deficits in CA1 pyramidal neurons of FSL rats were completely restored. Notably, the observed increase in spine density was attributable to regulation of both mushroom and long-thin spines. In contrast, ketamine had no effect on dendritic spine density in FRL rats. On the molecular level, ketamine normalized elevated levels of phospho-cofilin and the NMDA receptor subunits GluN2A and GluN2B and reversed homer3 deficiency in hippocampal synaptosomes of FSL rats. Taken together, our data suggest that rapid formation of new spines may provide an important structural substrate during the initial phase of ketamine’s antidepressant action.
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Acknowledgments
Centre for Stochastic Geometry and Advanced Bioimaging is supported by Villum Foundation. We gratefully acknowledge the support by the Core Facility Microscopy of the Institute of Molecular Biology (IMB) in Mainz, Germany and Ferruccio Bosetti for IT consulting. We thank Maiken Krogsbæk Mikkelsen for her assistance with microscopy.
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Funding was provided for G.T. by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation and a postdoctoral research grant from the Danish Council for Independent Research (DFF–5053-00103). L.M. was supported by CARIPLO Foundation (Biomedical Science for Young Scientists, Prog. 2014-1133). The work was supported by grants from Dagmar Marshall’s Foundation, Direktør Jacob Madsen and Hustru Olga Madsen’s Foundation, Aase og Ejnar Danielsen’s Foundation, Kong Christian den Tiendes Foundation, and Direktør Kurt Bønnelycke and Hustru Fru Grethe Bønnelycke’s Foundation.
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G.T., M.A., and H.K.M performed the experiments, analyzed and interpreted the results. G.T. and H.K.M. wrote the paper. All co-authors provided conceptual advice, commented on the manuscript, and approved the final version before submission.
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Treccani, G., Ardalan, M., Chen, F. et al. S-Ketamine Reverses Hippocampal Dendritic Spine Deficits in Flinders Sensitive Line Rats Within 1 h of Administration. Mol Neurobiol 56, 7368–7379 (2019). https://doi.org/10.1007/s12035-019-1613-3
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DOI: https://doi.org/10.1007/s12035-019-1613-3