PET imaging of pre-synaptic protein SV2A in Rett syndrome mouse model

Objectives: Rett syndrome is a rare neurological disorder resulting in intellectual disability caused by mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Altered neuronal morphology and reduced dendritic complexity have been observed in cell and animal models of Rett syndrome. The goal of this study was to use [¹¹C]UCB-J, a PET radioligand binding to the pre-synaptic protein SV2A, to assess changes in synaptic density in the Mecp2 knockout (Mecp2 KO) mice, a mouse model of Rett syndrome.

Methods: Two Mecp2 KO and two wild type littermate (WT) mice underwent [¹¹C]UCB-J scans using a Sophie G4 PET scanner. Dynamic images were acquired during 45 minutes after injection of the radiotracer (57.5±14.4μCi, 1.07±0.004 pg ) and reconstructed with 15 dynamic frames (six-1min, two-2min, seven-5min). Using FSL FLIRT the integrated PET image was normalized to the mouse MR brain template (Paxinos, 2001). The whole cortex volume of interest was created using the Paxinos mouse brain atlas. The body weight SUV was calculated using the cortical values from the last 15 minutes of the scan for the Mecp2 KO and the WT mice.

Results: SUV_BW data calculated using the cerebral cortex region from 30 to 45 minutes of the scan gave values of 1.21±0.21 for the WT mice and 0.52±0.13 for the mutant mice.

Conclusions: These preliminary results reveal decreased uptake of [¹¹C]UCB-J in the Rett syndrome mouse model are consistent with the hypothesis that the loss of Mecp2 gene may result in decreased synaptic density in the cerebral cortex. Studies are ongoing to increase the sample size that may inform future investigation into whether [¹¹C]UCB-J imaging can serve as a valid biomarker in individuals with Rett syndrome.

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