Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington's Disease: a Longitudinal PET Study

Impairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington's Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [¹¹C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age. Analyses of regional volume of distribution with an image-derived input function (V_{T (IDIF)}) and voxel-wise parametric V_{T (IDIF)} maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [¹¹C]ITDM V_{T (IDIF)} quantification revealed higher mGluR1 availability in the brain of HET mice compared to WT littermates (e.g. cerebellum: + 15.0%, + 17.9%, and + 17.6% at 6, 12, and 16 months, respectively; p < 0.001). In addition, an age-related decline in [¹¹C]ITDM binding independent of genotype was observed between 6 and 12 months. Voxel-wise analysis of parametric maps and post-mortem quantifications confirmed the elevated mGluR1 availability in HET mice compared to WT littermates. In conclusion, in vivo measurement of mGluR1 availability using longitudinal [¹¹C]ITDM PET imaging demonstrated higher [¹¹C]ITDM binding in extra-striatal brain regions during the course of disease in the Q175DN mouse model.