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

Abstract

IntroductionSeveral lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington's disease (HD). Using [ 18 F]MK-9470 and [1 8 F]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 brain morphology (MRI) and motor function. MethodsTen 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. ResultsIn R6/2 mice, CB1 receptor binding was decreased in comparison to WT in the bilateral caudateputamen, globus pallidus and thalamic nucleus at week 5 (-8.1%, p height =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 height =1.9.10 -5 ; Fig. 1). 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 height =1.5.10 -4 ; Fig. 2). 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. ConclusionsOur findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, that may play a detrimental 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.

Longitudinal Small-Animal PET Imaging of the zQ175 Mouse Model of Huntington Disease Shows In Vivo Changes of Molecular Targets in the Striatum and Cerebral Cortex

“…This is in line with recent human PET studies reporting a 50% reduction of binding of the PDE10A enzyme in the striatum of HD patients compared with controls (9,11). Additionally, a 70%-80% reduction in PDE10A BP ND by 12 wk of age in the R6/2 HD mouse model compared with WT has been reported using another PET radioligand for PDE10A, 18 F-JNJ42259152 (42).…”

A novel thermoregulatory role for PDE 10A in mouse and human adipocytes

“…Future studies can establish which splice variants of PDE10A are found in adipocytes and their respective subcellular distribution and roles in glucose uptake, lipolysis, and inducing gene expression. Our results further attest to the sensitivity of small‐animal PET studies in measuring changes in PDE10A levels in preclinical models of disease such as has recently been shown in a Huntington's disease mouse model (Ooms et al , 2014b). It is noteworthy that changes in PDE10A expression may differ within sub‐regions of the striatum in obesity.…”

Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity

“…PET can detect various molecular changes in HD gene expansion carriers before disease manifestation [128,129]. Currently, one of the most important biomarkers for patients with HD is PDE10A, which is highly expressed in MSNs, but not in interneurons [33,130,131,132,133]. PDE10A is a dual substrate that regulates cAMP/PKA signaling and hydrolyzes cAMP and cGMP with an approximately 20-fold higher affinity for cAMP [134].…”