Comprehensive Behavioral and Molecular Characterization of a New Knock-In Mouse Model of Huntington’s Disease: zQ175

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric manifestations. Since the mutation responsible for the disease was identified as an unstable expansion of CAG repeats in the gene encoding the huntingtin protein in 1993, numerous mouse models of HD have been generated to study disease pathogenesis and evaluate potential therapeutic approaches. Of these, knock-in models best mimic the human condition from a genetic perspective since they express the mutation in the appropriate genetic and protein context. Behaviorally, however, while some abnormal phenotypes have been detected in knock-in mouse models, a model with an earlier and more robust phenotype than the existing models is required. We describe here for the first time a new mouse line, the zQ175 knock-in mouse, derived from a spontaneous expansion of the CAG copy number in our CAG 140 knock-in colony [1]. Given the inverse relationship typically observed between age of HD onset and length of CAG repeat, since this new mouse line carries a significantly higher CAG repeat length it was expected to be more significantly impaired than the parent line. Using a battery of behavioral tests we evaluated both heterozygous and homozygous zQ175 mice. Homozygous mice showed motor and grip strength abnormalities with an early onset (8 and 4 weeks of age, respectively), which were followed by deficits in rotarod and climbing activity at 30 weeks of age and by cognitive deficits at around 1 year of age. Of particular interest for translational work, we also found clear behavioral deficits in heterozygous mice from around 4.5 months of age, especially in the dark phase of the diurnal cycle. Decreased body weight was observed in both heterozygotes and homozygotes, along with significantly reduced survival in the homozygotes. In addition, we detected an early and significant decrease of striatal gene markers from 12 weeks of age. These data suggest that the zQ175 knock-in line could be a suitable model for the evaluation of therapeutic approaches and early events in the pathogenesis of HD.

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…In fact, we showed a reduction in extracellular adenosine levels in the striatum of Tg51 rats and also of zQ175 knock-in mice, 171 a recently developed transgenic animal model of HD. 195 Unlike the Tg51 rats, we observed a downregulation of A 2A R in the zQ175 mice. 171 It is well accepted that under physiological conditions, the main source of extracellular adenosine production is the release of ATP by astroglial vesicles.…”

Integration-independent Transgenic Huntington Disease Fragment Mouse Models Reveal Distinct Phenotypes and Life Span in Vivo

“…In models of HD, the change in signaling for DARPP-32 occurs well before loss of neurons and therefore represents early events in neuronal dysregulation and dysfunction (55)(56)(57)(58)(59)(60)(61)(62). DARPP-32 expression in the striatum of N552-Q148 mice was significantly reduced (p Ͻ 0.01) when compared with B6, N463-Q148, N536-Q148, and N586-Q148 mice (Fig.…”

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease

“…Compromised exocytosis may result from reduced dopamine content per vesicle (Johnson et al, 2007), fewer vesicles, or disrupted mobilization of reserve vesicular pools (Ortiz et al, 2010). One possibility is that aggregates of the Htt protein, which can impair vesicular protein function (Morton et al, 2001;Li et al, 2003), disrupt vesicular mobilization, and dopamine release.…”