Sapap3 deletion causes dynamic synaptic density abnormalities: a longitudinal [11C]UCB-J PET study in a model of obsessive–compulsive disorder-like behaviour

Abstract

Background Currently, the evidence on synaptic abnormalities in neuropsychiatric disorders—including obsessive–compulsive disorder (OCD)—is emerging. The newly established positron emission tomography (PET) ligand ((R)-1-((3-((11)C-methyl-(11)C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([11C]UCB-J) provides the opportunity to visualize synaptic density changes in vivo, by targeting the synaptic vesicle protein 2A (SV2A). Here, we aim to evaluate such alterations in the brain of the SAP90/PSD-95-associated protein 3 (Sapap3) knockout (ko) mouse model, showing an abnormal corticostriatal neurotransmission resulting in OCD-like behaviour. Methods Longitudinal [11C]UCB-J µPET/CT scans were acquired in Sapap3 ko and wildtype (wt) control mice (n = 9/group) to study SV2A availability. Based on the Logan reference method, we calculated the volume of distribution (VT(IDIF)) for [11C]UCB-J. Both cross-sectional (wt vs. ko) and longitudinal (3 vs. 9 months) volume-of-interest-based statistical analysis and voxel-based statistical parametric mapping were performed. Both [11C]UCB-J ex vivo autoradiography and [3H]UCB-J in vitro autoradiography were used for the validation of the µPET data. Results At the age of 3 months, Sapap3 ko mice are already characterized by a significantly lower SV2A availability compared to wt littermates (i.a. cortex − 12.69%, p < 0.01; striatum − 14.12%, p < 0.001, thalamus − 13.11%, p < 0.001, and hippocampus − 12.99%, p < 0.001). Healthy ageing in control mice was associated with a diffuse and significant (p < 0.001) decline throughout the brain, whereas in Sapap3 ko mice this decline was more confined to the corticostriatal level. A strong linear relationship (p < 0.0001) was established between the outcome parameters of [11C]UCB-J µPET and [11C]UCB-J ex vivo autoradiography, while such relationship was absent for [3H]UCB-J in vitro autoradiography. Conclusions [11C]UCB-J PET is a potential marker for synaptic density deficits in the Sapap3 ko mouse model for OCD, parallel to disease progression. Our data suggest that [11C]UCB-J ex vivo autoradiography is a suitable proxy for [11C]UCB-J PET data in mice.

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

“…[ 11 C]UCB-J has now been used in monkeys ( Nabulsi et al, 2016 ), pigs ( Thomsen et al, 2020 ), mice ( Bertoglio et al, 2020 ), rats ( Thomsen et al, 2021b ), and humans ( Finnema et al, 2016 ) and show favourable brain penetration, fast uptake and acceptable washout kinetics. In rats and mice, various kinetic modelling was performed using an arterial blood sampling scheme or image-derived input function (IDIF) from the heart ( Bertoglio et al, 2020 ; Glorie et al, 2020 ; Thomsen et al, 2021b ). The 1TCM and 2TCM both work favourably with [ 11 C]UCB-J using the heart as an IDIF ( Bertoglio et al, 2020 ; Glorie et al, 2020 ).…”

“…In rats and mice, various kinetic modelling was performed using an arterial blood sampling scheme or image-derived input function (IDIF) from the heart ( Bertoglio et al, 2020 ; Glorie et al, 2020 ; Thomsen et al, 2021b ). The 1TCM and 2TCM both work favourably with [ 11 C]UCB-J using the heart as an IDIF ( Bertoglio et al, 2020 ; Glorie et al, 2020 ). The use of IDIF and whole-brain normalisation allows longitudinal studies in rodents since blood sampling often is laborious and error-prone.…”

Validation, kinetic modeling, and test-retest reproducibility of [18F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice

“…Given the instrumental role of preclinical models in understanding neuropsychiatric and neurodegenerative disorders in parallel to the broad spectrum of diseases characterized by synaptic dysfunction, we previously described the application of [ 11 C]UCB-J in mice 15 and the utility of [ 11 C]UCB-J PET imaging in preclinical models to significantly advance our understanding of the pathophysiology and diagnosis of neurological disorders, including Huntington’s disease, 16 obsessive-compulsive disorder, 17 and spinal cord injury. 18 …”

Imaging Synaptic Density: The Next Holy Grail of Neuroscience?

“…In psychiatric research, [ 11 C]UCB-J has been used to measure synaptic density deficits in the Sapap3 knockout model of obsessive-compulsive disorder, through a longitudinal PET study in which an early decrease in radiotracer binding was reported in several brain regions of this model, including in the cortex, striatum, thalamus, and hippocampus (Glorie et al, 2020).…”