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Quantitative monitoring of ketamine’s impact on synaptic density using 11C-UCB-J PET imaging in the corticosterone mouse model of anxiety/depression

Molecular Psychiatry (2025)Cite this article

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Abstract

Ketamine was shown to promote synaptogenesis, which is thought to account for its antidepressant effects through the restoration of lost synaptic connections observed in depression. PET imaging using 11C-UCB-J, a radiotracer targeting the synaptic vesicle protein 2 A (SV2A), was investigated as a translational method to monitor ketamine-induced changes in synaptic density in the corticosterone (CORT) mouse model of anxiety/depression. Male CORT and healthy control mice received either a single dose of ketamine (10 mg/kg, i.p) or a repeated-dose regimen (3 doses in total). Brain PET imaging was performed either 24 h after the single dose or 1 or 3 weeks after the repeated-dose regimen to estimate the binding of 11C-UCB-J in each condition. A global decrease in the binding of 11C-UCB-J was observed in CORT mice compared to control mice, indicating synaptic loss. In CORT mice, behavioral experiments showed antidepressant effects of ketamine 24 h after a single dose, although no significant changes in 11C-UCB-J binding could be observed at this time point. Three weeks after the repeated dose regimen, ketamine restored the binding of 11C-UCB-J in CORT mice to the level of age-matched untreated healthy controls. The reversal of synaptic loss was associated with delayed antidepressant effects in behavioural tests. Ex vivo expression of SV2A protein measured under different conditions was strongly correlated with the in vivo binding of 11C-UCB-J and the postsynaptic marker PSD95. These results support the molecular interpretation of SV2A PET imaging to monitor drug-induced synaptogenesis as a determinant of antidepressant efficacy from a translational perspective.

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Fig. 1: PET study design.
Fig. 2: Behavioral tests were conducted to address the early and delayed impact of ketamine in control mice and in the corticosterone (CORT) mouse model of depression.
Fig. 3: Impact of ketamine on 11C-UCB-J brain PET kinetics in control mice and in the CORT mouse model of anxiety/depression.
Fig. 4: Voxel-to-voxel comparison of VT-maps obtained after one day (1d), 1 week (1w), or 3 weeks (3w) after ketamine in age-matched control and the corticosterone (CORT) mouse model of depression.
Fig. 5: In vivo / ex vivo correlation of SV2A protein levels and corresponding 11C-UCB-J brain PET data.

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Data availability

The data supporting this study’s findings are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Maud Goislard and Sophie Amargier-Barrial for their technical support during the preclinical study. We also thank Stephane Demphel and Françoise Hinnen for producing 11C-UCB-J. This work is funded by the French National Agency for Research (Grant ANR-22-CE17-0015) and was performed on a platform member of the France Life Imaging network (grant ANR-11-INBS-0006).

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Author notes

  1. These authors contributed equally: Denis J. David, Nicolas Tournier.

Authors and Affiliations

  1. Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), Service Hospitalier Frédéric Joliot, Orsay, France

    Cassandre Corvo, Sébastien Goutal, Sarah Leterrier, Fabien Caille, Wadad Saba, Vincent Lebon, Michel Bottlaender, Claire Leroy & Nicolas Tournier

  2. Université Paris-Saclay, UVSQ, Centre de recherche en Epidémiologie et Santé des Populations (CESP), UMR 1018, CESP-Inserm, Team MOODS, Faculté de Pharmacie, Bâtiment Henri Moissan, Orsay, France

    Indira Mendez-David & Denis J. David

  3. Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations (CESP), UMR1018, CESP-Inserm, Team MOODS, Faculté de Médecine, Le Kremlin-Bicêtre, France

    Romain Colle & Emmanuelle Corruble

  4. Service Hospitalo-Universitaire de Psychiatrie, Hôpital de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France

    Romain Colle & Emmanuelle Corruble

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Contributions

RC, CL, DJD, and NT obtained funding and resources to conduct the study. CC, CL, DJD, IMD, SG, and NT conceived and planned the study. CC and IMD have developed and applied the model and behavioral assessments. FC has developed and supervised the synthesis of 11C-UCB-J. CC, SG, and SL conducted the PET imaging experiments and analyzed the data. The results were interpreted by FC, WS, SG, NT, CL, EC, VL, MB, RC, DJD, and IMD. CC and NT wrote the manuscript and made the figures. All authors revised and approved the manuscript.

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Correspondence to Nicolas Tournier.

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Corvo, C., Goutal, S., Mendez-David, I. et al. Quantitative monitoring of ketamine’s impact on synaptic density using 11C-UCB-J PET imaging in the corticosterone mouse model of anxiety/depression. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03369-3

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