Abstract
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 (VT (IDIF)) and voxel-wise parametric VT (IDIF) maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [11C]ITDM VT (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.
Highlights
Glutamate is the primary excitatory neurotransmitter in the central nervous system and exerts its action through both ionotropic and metabotropic receptors
In Vivo mGluR type 1 (mGluR1) Availability Was Higher in Huntington’s Disease (HD) Mice
HET mice were characterized by elevated brain [11C]ITDM VT (IDIF) values compared to WT littermates (Fig. 2)
Summary
Glutamate is the primary excitatory neurotransmitter in the central nervous system and exerts its action through both ionotropic and metabotropic receptors. Group I metabotropic glutamate receptors (mGluRs) are post-synaptic G proteincoupled receptors and include mGluR type 1 (mGluR1) and type 5 (mGluR5) [1]. Intracellular Ca2+ release and protein kinase C activation [2] Impairment in their functionality can cause altered glutamate signalling and excitotoxicity, a reason why both mGluR1 and mGluR5 have been associated with several neurological disorders, including Huntington’s Disease (HD) [3, 4]. HD is an inherited autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine (CAG) repeat in the exon 1 of the HTT gene [5] This mutated gene translates to mutant huntingtin (mHTT), which is the causative agent of the disease. As a consequence of mHTT accumulation, neuronal dysfunction and death occurs, leading to progressive motor, psychiatric, and cognitive impairments in individuals with HD [6, 7]
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