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Open Access 01-12-2020 | Obsessive-Compulsive Disorder | Original research

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

Authors: Dorien Glorie, Jeroen Verhaeghe, Alan Miranda, Stef De Lombaerde, Sigrid Stroobants, Steven Staelens

Published in: EJNMMI Research | Issue 1/2020

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 (V_T(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.

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Title: Sapap3 deletion causes dynamic synaptic density abnormalities: a longitudinal [11C]UCB-J PET study in a model of obsessive–compulsive disorder-like behaviour
Authors: Dorien Glorie
Jeroen Verhaeghe
Alan Miranda
Stef De Lombaerde
Sigrid Stroobants
Steven Staelens
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keywords: Obsessive-Compulsive Disorder
Positron Emission Tomography
Published in: EJNMMI Research / Issue 1/2020
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-020-00721-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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