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Progression of obsessive compulsive disorder-like grooming in Sapap3 knockout mice
Journal Contribution - Journal Article
Subtitle:a longitudinal [11C]ABP688 PET study
We aimed to evaluate [3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-0-C-11-methyloxime] ([C-11]ABP688) small animal positron emission tomography (mu PET) as a biomarker to visualize possible longitudinal changes in metabotropic glutamate receptor 5 (mGluR5) availability in the brain of SAP90/PSD-95 associated protein 3 (Sapap3) knockout (ko) mice, showing obsessive compulsive disorder (OCD)-like behavior. Methods: Alongside the assessment of grooming, we performed [C-11]ABP688 mu PET/CT imaging in wildtype (wt; n=10) and ko (n=11) mice both at 3 and 9 months. Using the simplified reference tissue method (SRTM), the nondisplaceable binding potential (BPND) was calculated representing the in vivo availability of the metabotropic glutamate receptor 5 (mGluR5) in the brain with the cerebellum as a reference region. Longitudinal voxel-based statistical parametric mapping (SPM) was performed on BPND images. Results were verified using [C-11]ABP688 ex vivo autoradiography, [H-3]ABP688 in vitro autoradiography, and mGluR5 immunohistochemistry. Results: Cross-sectional comparisons revealed significantly increased grooming parameters in ko animals, at both time points. A significant longitudinal increase in % grooming duration (+268.25%; p<0.05) reflected aggravation of this behavior in ko mice. [C-11]ABP688 mu PET revealed significantly lower mGluR5 availability in the cortex, striatum, hippocampus, and amygdala of ko mice at both ages. A significant longitudinal BPND decline was present for ko mice (p<0.01: cortex -17.14%, striatum -19.82%, amygdala -23.57%; p<0.05: hippocampus -15.53%), which was confirmed by SPM (p<0.01). Conclusion: Sapap3 ko mice show a decline in mGluR5 availability in OCD relevant brain regions parallel to the worsening of OCD-like behavior. This demonstrates a potential role for [C-11]ABP688 PET as a biomarker to monitor disease progression in vivo.
Number of pages: 9
Keywords:Neurosciences & psychopharmacology, Pharmacology & toxicology