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

Abstract

Since the discovery of the HTT gene in 1993, numerous animal models have been developed to study the progression of Huntington disease (HD) and to evaluate potential new therapeutics. In the present study, we used small-animal PET to characterize the expression of molecular targets in the recently reported HD animal model, the zQ175 mouse model. Male heterozygous zQ175 (Htt/190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D receptor radioligand C-raclopride, the PDE10A radioligandF-MNI-659, the dopamine D receptor radioligand C-NNC 112, and the 5-HT radioligand C-MDL 100907 at 6 and 9 mo of age. The outcome measure was the binding potential (), using the cerebellum as the reference region. Selected regions of interest were the striatum for all radioligands and additionally the striatum, rostral cortex, caudal cortex, and hippocampus for C-NNC 112 andC-MDL 100907. At 6 mo of age, the in the striatum was lower in zQ175 than WT animals by 40% for C-raclopride, by 52% forF-MNI-659, by 28% for C-NNC, and by 11% forC-MDL 100907. In the rostral cortex, D receptor binding was 22% lower in zQ175 than WT animals. We found an overall reduction in D and 5-HT binding in the hippocampus of zQ175 compared with WT animals. The ofC-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further reduction of D, D, and 5-HT in the striatum, whereas PDE10A reached a plateau. Cortical markers were also slightly further decreased at 9 mo in zQ175 animals. Our study indicates a marked reduction of ligand binding to D and D and 5-HT receptors as well as loss of PDE10A enzyme in the striatum of zQ175 mice as compared with WT animals, in agreement with data obtained in clinical PET studies of patients with HD. The zQ175 mouse model recapitulates the expression pattern seen in humans with HD and may have value in further elucidating pathophysiologic events and therapeutic strategies.

MR-based spatial normalization improves [18F]MNI-659 PET regional quantification and detectability of disease effect in the Q175 mouse model of Huntington’s disease

“…[ 18 F]MNI-659, (2-(2-(3-(4-(2-[ 18 F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione) and [ 18 F]JNJ42259152) [ 9 , 10 ] allowed to investigate in vivo changes of PDE10A by means of positron emission tomography (PET). HD-related PDE10A decrease at early disease stage has been confirmed by several in vivo studies both in mouse models of HD [ 11 – 13 ] and patients with HD [ 14 , 15 ].…”

Longitudinal Characterization of mGluR5 Using 11C-ABP688 PET Imaging in the Q175 Mouse Model of Huntington Disease

“…In addition, we quantified mGluR5 and neuronal density in a satellite cohort of 6-moold mice by means of immunohistochemistry. This animal model displays motor, cognitive, molecular, and electrophysiologic abnormalities, including an in vivo temporal decrease in different striatal markers such as dopamine receptors D 1 and D 2/3 , similar to patients with Huntington disease (14)(15)(16)(17).…”

Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington’s Disease: a Longitudinal PET Study

“…Since C57BL/6J mice present sporadic congenital portosystemic shunt [20], animals were screened before inclusion in the study to avoid this variable as confounding factor. This mouse model of HD exhibits motor, cognitive, molecular, and electrophysiological abnormalities, including in vivo decrease in several striatal markers and HD hallmarks similarly to patients with HD [16,17,[21][22][23][24]. Only HET mice were included in the study to better resemble the clinical condition as homozygousity is rare in patients with HD.…”