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 – November 18, 2025
Source: PubMed
Summary
Depression often involves a loss of crucial brain connections. Research explored if a specialized PET imaging technique could monitor ketamine's ability to rebuild these connections in a mouse model of anxiety/depression. Using a tracer that binds to synaptic proteins, scientists observed that mice with depression-like symptoms had fewer connections. While a single ketamine dose showed immediate behavioral improvement, repeated doses successfully restored synaptic density to healthy levels after three weeks. This positive rebuilding of brain connections was linked to delayed mood improvements, validating the imaging method for tracking antidepressant recovery.
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.