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

Area of Science:

• Neuroscience
• Molecular Biology
• Medical Imaging

Background:

• Huntington disease (HD) is a neurodegenerative disorder with early molecular alterations.
• Endocannabinoid and phosphodiesterase 10A (PDE10A) signaling pathways are implicated in HD pathogenesis.

Purpose of the Study:

• To investigate in vivo cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in a mouse model of HD.
• To correlate these molecular changes with glucose metabolism, brain morphology, and motor function.

Main Methods:

• Utilized small-animal positron emission tomography (PET) with [(18)F]MK-9470 and [(18)F]JNJ42259152 to quantify CB1 receptor and PDE10A binding.
• Assessed glucose metabolism using [(18)F]FDG PET and brain morphology via microMRI.
• Evaluated motor function in presymptomatic, early symptomatic, and late symptomatic R6/2 HD mice and wild-type controls.

Main Results:

• Progressive decline in CB1 receptor binding observed in R6/2 mice, particularly in the caudate-putamen, globus pallidus, and hippocampus.
• Significant decrease in PDE10A binding potential in R6/2 mice, becoming apparent at early and late symptomatic stages.
• CB1 receptor and PDE10A binding changes correlated with motor function deficits, but not with striatal volume changes.

Conclusions:

• Early regional dysfunctions in endocannabinoid and PDE10A signaling occur in HD, potentially driving disease progression.
• PET quantification of in vivo CB1 and/or PDE10A binding may serve as valuable early biomarkers for Huntington disease.
• Subtle motor deficits in HD may manifest earlier than previously recognized.