Quantitative monitoring of ketamine's impact on synaptic density using 11C-UCB-J PET imaging in the corticosterone mouse model of anxiety/depression.
Cassandre Corvo, Sébastien Goutal, Indira Mendez-David, Sarah Leterrier, Fabien Caille, Wadad Saba, Romain Colle, Emmanuelle Corruble, Vincent Lebon, Michel Bottlaender, Claire Leroy, Denis J David, Nicolas Tournier
Molecular psychiatry November 18, 2025 DOI: 10.1038/s41380-025-03369-3 via PubMed
Summary
AI-generated from the abstractIn a mouse model of anxiety/depression, a single dose of ketamine produced rapid antidepressant effects in behavior tests, but no change in synaptic density was detected by PET imaging 24 hours later. After three weekly doses, ketamine restored synaptic density to healthy control levels, an effect that coincided with delayed antidepressant effects. The PET tracer 11C-UCB-J reliably tracked these changes, and its binding correlated with levels of synaptic proteins. The findings support using SV2A PET imaging to monitor drug-induced rebuilding of brain connections as a marker of antidepressant efficacy.
Study at a glance
| Characteristics | Animal model Peer reviewed |
|---|---|
| Population | Male CORT (corticosterone-treated) and healthy control mice |
| Intervention | Ketamine |
| Dose | 10 mg/kg |
| Duration | 24 hours after single dose; 1 or 3 weeks after repeated-dose regimen |
| Keywords | Ketamine ketamine Single ketamine dose Repeated doses Neuroplasticity brain connections Crucial brain connections |
| Citations | 1 |
| Key finding | Repeated ketamine doses restored synaptic density in the depression mouse model, as measured by PET imaging, and this restoration was associated with delayed antidepressant effects. |
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.