Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.

Purpose: Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington disease (HD). Using [18F]MK-9470 and [18F]JNJ42259152 small-animal PET, we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in vivo in pre-, early- and late symptomatic HD (R6/2) mice, in relation to glucose metabolism ([18F]FDG PET), brain morphology (MRI) and motor function. 

Methods: Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4 and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to Paxinos space and analyzed voxel-wise. Volumetric microMRI imaging was performed to assess HD pathology. 

Results: In R6/2 mice, CB1 receptor binding was decreased in comparison to WT in a cluster comprising the bilateral caudate-putamen, globus pallidus and thalamic nucleus at week 5 (-8.1±2.6%; p=1.7.10-5). Longitudinal follow-up showed further progressive decline compared to controls in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior colliculus, thalamic nucleus and cerebellum (late vs. presymptomatic age: -13.7±3.1% for R6/2 and +1.5±4.0% for WT; p=1.9.10-5). In R6/2 mice, PDE10A binding potential also decreased over time, to reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1±1.9% for R6/2 and +2.1±2.7% for WT; p=1.5.10-4). The observed changes in CB1 receptor and PDE10A binding were correlated to anomalies exhibited by R6/2 animals in motor function, while no correlation was found with MRI-based striatal volume. 

Conclusion: Our findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, that may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide evidence of subtle motor deficits at earlier stages than previously described.