Abstract
Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, [1]) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al [1], and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease.
Highlights
Huntington’s disease (HD) is an autosomal neurodegenerative disorder characterized by motor, behavioral, cognitive and metabolic dysfunction, and caused by an expansion of a CAG trinucleotide repeat region located in exon 1 of the huntingtin gene (HTT) on chromosome 4 [2]
Disease onset in the BAC or YAC transgenic mouse strains expressing full-length mutant Htt (mHtt) varies from 8 weeks to 4 months, depending on the strain and the number of the CAG repeats, and they display variable onset and severity of various signs depending on the strain [11]
KI mouse models developed to date typically show more subtle behavioral, histopathological, and molecular phenotypes compared to the transgenic models that overexpress mHtt [12,13], rendering these models less suited to preclinical compound testing where life cycle and numbers of mice are critical
Summary
Huntington’s disease (HD) is an autosomal neurodegenerative disorder characterized by motor, behavioral, cognitive and metabolic dysfunction, and caused by an expansion of a CAG trinucleotide repeat region located in exon 1 of the huntingtin gene (HTT) on chromosome 4 [2]. The first transgenic HD mouse models expressed truncated fragments of mHtt [10] These mice, such as the R6/2 strains, have rapidly developing disease signs including decreased body weight, motor and cognitive deficits starting as early as 6–8 weeks of age, and early mortality [10]. The CAG140 mouse (a KI line with 140 CAG repeats; [14]) displays early onset behavioral deficits with striatal neuronal loss and decreased volumes later [14,15] but the robustness of these deficits may not be sufficient for preclinical compound testing studies [for review see 12]. Robust, dose-dependent, progressive, and early-onset alterations in these endpoints, which may prove useful to further investigate biological pathways affected by mHtt and to evaluate pharmacological or genetic interventions to modify disease onset and progression
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