title: 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.Methods:Male heterozygous zQ175 (Htttm1Mfc/190JChdi, CHDI-81003003) and wild-type (WT, C57BL/6J) animals were imaged with the dopamine D2receptor radioligand11C-raclopride, the PDE10A radioligand18F-MNI-659, the dopamine D1receptor radioligand11C-NNC 112, and the 5-HT2Aradioligand11C-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 for11C-NNC 112 and11C-MDL 100907.Results:At 6 mo of age, theBPNDin the striatum was lower in zQ175 than WT animals by 40% for11C-raclopride, by 52% for18F-MNI-659, by 28% for11C-NNC, and by 11% for11C-MDL 100907. In the rostral cortex, D1receptor binding was 22% lower in zQ175 than WT animals. We found an overall reduction in D1and 5-HT2Abinding in the hippocampus of zQ175 compared with WT animals. TheBPNDof11C-MDL 100907 in the caudal cortex was also lower in zQ175 WT animals. At 9 mo, there was a slight further reduction of D1, D2, and 5-HT2ABPNDin 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 D1and D2and 5-HT2Areceptors 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.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and Jenny.Haggkvist@ki.se.
authors.forename: Jenny
authors.initials: J
authors.lastname: Häggkvist
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Lenke
authors.initials: L
authors.lastname: Tari
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Marie
authors.initials: M
authors.lastname: Svedberg
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Anton
authors.initials: A
authors.lastname: Forsberg
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Sangram
authors.initials: S
authors.lastname: Nag
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey.
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Mrzljak
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006579:Heterozygote; D006816:Huntington Disease / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D017072:Neostriatum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism
chemical_list: D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3
keywords: PDEA10A enzyme; PET; animal imaging; dopamine; neurology; serotonin