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

摘要

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. Methods: Male heterozygous zQ175 (Htt(tm1Mfc)/190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D-2 receptor radioligand C-11-raclopride, the PDE10A radioligand F-18-MNI-659, the dopamine D-1 receptor radioligand (CNNC)-C-11 112, and the 5-HT2A radioligand C-11-MDL 100907 at 6 and 9 mo of age. The outcome measure was the binding potential (BPND), 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-11-NNC 112 and C-11-MDL 100907. Results: At 6 mo of age, the BPND in the striatum was lower in zQ175 than WT animals by 40% for 11C-raclopride, by 52% for F-18-MNI-659, by 28% for C-11-NNC, and by 11% for C-11-MDL 100907. In the rostra! cortex, D-1 receptor binding was 22% lower in zQ175 than WT animals. We found an overall reduction in D-1 and 5-HT2A binding in the hippocampus of zQ175 compared with WT animals. The BPND of C-11-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further reduction of D-1, D-2, and 5-HT2A BPND in the striatum, whereas PDE10A reached a plateau. Cortical markers were also slightly further decreased at 9 mo in zQ175 animals. Conclusion: Our study indicates a marked reduction of ligand binding to D-1 and D-2 and 5-HT2A 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.