Progression of obsessive compulsive disorder-like grooming in Sapap3 knockout mice: A longitudinal [11C]ABP688 PET study

Glorie, Dorien; Verhaeghe, Jeroen; Miranda, Alan; Kertész, István; wyffels, Leonie; Stroobants, Sigrid; Staelens, Steven

doi:10.1016/j.neuropharm.2020.108160

Cited by 12 publications

(4 citation statements)

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“…Already at an early age this model shows a marked increase in grooming frequency, despite the absence of the typical skin lesions. In addition, an exacerbation of this behaviour was demonstrated, reflected by an important increase in grooming duration with ageing [27]. This is indicative of a dynamic pathological process in the Sapap3 ko mouse brain.…”

Section: Introductionmentioning

confidence: 84%

“…In the present study, we aimed to describe cross-sectional differences in the synaptic density between wt controls and Sapap3 ko mice, which progress to severe compulsive-like grooming behaviour [27], thereby using the newly established PET marker [ 11 C]UCB-J. Also, we studied longitudinal changes in this marker during grooming aggravation, for each genotype separately.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…PET studies in sapap3 knockout mice, which show progressive exaggeration of grooming behavior that models obsessive compulsive disorder, showed widespread 20% decreases in [ 11 C]ABP688 ( 82 ) binding in association with their worsening behavior at nine months of age [ 169 ]. In this case, the decline in binding seen with small animal PET was not captured by semiquantitative autoradiography with [ 3 H]ABP688 in vitro or by mGuR5 immunohistochemisty.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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“…Mice with mutated versions of SAPAP3 , (also known as DLGAP3 ) exhibit OCD-like behavior, including excessive grooming, increased anxiety, and abnormal corticostriatal neurotransmission, which was significantly reduced after fluoxetine treatment (Burguière, Monteiro, Feng, & Graybiel, 2013; Glorie et al, 2020; Hadjas, Lüscher, & Simmler, 2019; Manning, Dombrovski, Torregrossa, & Ahmari, 2019; van den Boom, Mooij, Misevičiūtė, Denys, & Willuhn, 2019; Welch et al, 2007). SAPAP3 belongs to the highly homologous SAPAP family proteins, which are components of the postsynaptic density that interact with multiple members of proteins from the PSD-95 and Shank families.…”

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confidence: 99%

Association of SAPAP3 allelic variants with symptom dimensions and pharmacological treatment response in obsessive–compulsive disorder.

Naaz¹,

Balachander²,

Murthy³

et al. 2022

Experimental and Clinical Psychopharmacology

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Progression of obsessive compulsive disorder-like grooming in Sapap3 knockout mice: A longitudinal [11C]ABP688 PET study

Cited by 12 publications

References 48 publications

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

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

A Review of Molecular Imaging of Glutamate Receptors

Association of SAPAP3 allelic variants with symptom dimensions and pharmacological treatment response in obsessive–compulsive disorder.

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