Abstract
BackgroundCurrently, 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.MethodsLongitudinal [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.ResultsAt 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.
Highlights
The evidence on synaptic abnormalities in neuropsychiatric disorders—including obsessive–compulsive disorder (OCD)—is emerging
For validation purposes and as one of the first, we aim to perform ex vivo 11C autoradiography where multiple animals are injected with rapidly decaying [11C]UCB-J in tracer dose conditions [47] complementary to the traditional in vitro [3H] autoradiography where tissue slides are incubated with the tracer
This is the first study to verify whether [11C]UCB-J ex vivo autoradiography is suitable to validate [11C]UCB-J Small-animal positron emission tomography (μPET) results
Summary
The evidence on synaptic abnormalities in neuropsychiatric disorders—including obsessive–compulsive disorder (OCD)—is emerging. Patients are highly impaired in their daily functioning due to persistent intrusive thoughts (obsessions) and by Glorie et al EJNMMI Res (2020) 10:140 engaging in time-consuming repetitive actions (compulsions) [2] to reduce the anxiety about their obsessions The severity of this disorder is reflected by its ranking in the top ten causes of illness-related disability based on quality of life and lost earnings proposed by the World Health Organization [3]. The barriers associated with clinical OCD research can be circumvented via the use of animal models They provide the opportunity to further unravel and dissect the pathological mechanisms underlying compulsive(like) behaviours [11,12,13,14,15,16,17]
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