Characterization of Neurophysiological and Behavioral Changes, MRI Brain Volumetry and 1H MRS in zQ175 Knock-In Mouse Model of Huntington's Disease

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.

Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington's Disease Model Mice

“…Kir4.1 channels are astrocyte enriched and involved in K ϩ homeostasis (Kofuji and Newman, 2004;Sibille et al, 2015), along with other molecules (Larsen et al, 2014). Alterations in HD model mice occurred at stages with little or no evidence of accompanying astrogliosis (Mangiarini et al, 1996;Ben Haim et al, 2015), which is similar to observations on the lack of astrogliosis during early stages of the human disease (Faideau et al, 2010).…”

“…Kir4.1 channels are astrocyte enriched and involved in K ϩ homeostasis (Kofuji and Newman, 2004;Sibille et al, 2015), along with other molecules (Larsen et al, 2014). Alterations in HD model mice occurred at stages with little or no evidence of accompanying astrogliosis (Mangiarini et al, 1996;Ben Haim et al, 2015), which is similar to observations on the lack of astrogliosis during early stages of the human disease (Faideau et al, 2010). Also consistent with the human disease, astrogliosis increased dramatically at late stages of pathology in R6/2 and Q175 mice at time points associated with overt neurodegeneration and striatal tissue loss (Mangiarini et al, 1996;Faideau et al, 2010;.…”

“…HD is caused by an expanded polyglutamine repeat localized to the N-terminal region of the huntingtin protein (HTT) that causes intracellular accumulation and aggregation of mutant huntingtin (mHTT) (Mangiarini et al, 1996). The molecular, cellular, and circuit mechanisms that produce disease phenotypes remain incompletely understood (Waldvogel et al, 2015), although important progress has been made by focusing on mHTT expression within neurons of the corticostriatal pathway (Plotkin and Surmeier, 2015).…”

SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

“…Importantly, it has been shown that retromer also interacts with HTT protein (35) and regulates local NMDAR recycling in dendrites (36). Loss of retromer activity can cause diminished NMDA currents (36), progressive synaptic dysfunction, and neuronal degeneration (81), which are reminiscent of the phenotypes reported in HD mouse models (31,50,55).…”

“…To assess whether trafficking and surface presentation of NR2A subunits is perturbed in HD MSNs, we utilized the zQ175 mouse model of HD, which includes ~188 CAG repeats contained within a chimeric human/mouse exon 1 of murine HTT gene (30) and has been well established as a robust mouse model to study molecular mechanisms and therapeutic interventions of HD (30)(31)(32)(33)(34). Here, using quantitative analysis of immuno-electron microscopy (EM), we demonstrate that in symptomatic zQ175 mice, NR2A labeling is significantly reduced on the dendritic plasma membrane and at the synapses of MSNs and it becomes more restricted to the cytoplasm of MSNs.…”