Comparison of Phosphodiesterase 10A, Dopamine Receptors D1 and D2 and Dopamine Transporter Ligand Binding in the Striatum of the R6/2 and BACHD Mouse Models of Huntington's Disease
Affiliations: Department of Neuroscience, Amgen Inc., Thousand Oaks, CA, USA | South San Francisco, CA, USA | UCI Memory Impairments and Neurological Disorders Institute, CA, USA | Departments of Neurobiology and Behavior, and Psychiatry and Human Behavior, University of California, Irvine, CA, USA
Note: [] Correspondence to: Silke Miller, PhD., Department Neuroscience, Amgen Inc., One Amgen Center Dr., MS 29-2-B, Thousand Oaks, CA, USA. Tel.: +1 805 313 5277; E-mail: [email protected]
Note: [] Current address: ADRX, Westlake Village, CA, USA.
Abstract: Background: Phosphodiesterase 10A (PDE10A) is expressed at high levels in the striatum and has been proposed both as a biomarker for Huntington's disease pathology and as a target for intervention. Objective: PDE10A radiotracers have been successfully used to measure changes in binding density in Huntington's disease patients, but little is known about PDE10A binding in mouse models that are used extensively to model pathology and test therapeutic interventions. Methods: Our study investigated changes in PDE10A binding using the selective tracer 3H-7980 at specific ages of two Huntington's disease transgenic mouse models: R6/2, a short-lived model carrying exon-1 of mutant HTT and BACHD, a longer-lived model carrying full-length mutant HTT. PDE10A binding was compared to binding of known markers of striatal atrophy in Huntington's disease, e.g. dopamine transporter (DAT) and dopamine receptors D1 and D2. Results: We found that in the R6/2 model at 6 weeks of age, mice showed high variability of binding, however binding of all ligands was significantly decreased at 8 and 12 weeks of age. In contrast, no changes were detectable in the BACHD model at 8, 10 or 12 month of age. Conclusions: These findings suggest that radiotracer binding of PDE10A, DAT, D1 and D2 receptor in the R6/2 model may be a good indicator of striatal pathological changes that are observed in Huntington's disease patients, and that the first 12 months in the BACHD model may be more reflective of early stages of the disease.
