Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington's disease

Abstract

A long-term goal of modeling Huntington's disease (HD) is to recapitulate the cardinal features of the disease in mice that express both mutant and wild-type (WT) huntingtin (Htt), as HD commonly manifests as a heterozygous condition in humans, and loss of WT Htt is associated with loss-of-function. In a new heterozygous Q175 knock-in (KI) mouse model, we performed an extensive evaluation of motor and cognitive functional deficits, neuropathological and biochemical changes and levels of proteins involved in synaptic function, the cytoskeleton and axonal transport, at 1-16 months of age. Motor deficits were apparent at 6 months of age in Q175 KI mice and at that time, postmortem striatal gamma-aminobutyric acid (GABA) levels were elevated and mutant Htt inclusions were present throughout the brain. From 6 months of age, levels of proteins associated with synaptic function, including SNAP-25, Rab3A and PSD-95, and with axonal transport and microtubules, including KIF3A, dynein and dynactin, were altered in the striatum, motor cortex, prefrontal cortex and hippocampus of Q175 KI mice, compared with WT levels. At 12-16 months of age, Q175 KI mice displayed motor and cognitive deficits, which were paralleled at postmortem by striatal atrophy, cortical thinning, degeneration of medium spiny neurons, dense mutant Htt inclusion formation, decreased striatal dopamine levels and loss of striatal brain-derived neurotrophic factor (BDNF). Data from this study indicate that the heterozygous Q175 KI mouse represents a realistic model for HD and also provides new insights into the specific and progressive synaptic, cytoskeletal and axonal transport protein abnormalities that may accompany the disease.

Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease

“…2D, E). The timing of BDNF level reduction in the striatum correlates with the onset of motor behavior deficits in this line of HD mouse model (Smith et al, 2014). Notably, no significant decrease of mBDNF is detected in the hippocampus and the cortex at 6 months of age (about 8.84% and 3.34% reduction, respectively, P >0.05) (Fig.…”

“…In terms of pathology, homozygous mice have mutant huntingtin inclusions/aggregates (~2–4 months of age), early and significant decrease of striatal gene markers (~3 months of age) and decreased neuronal cell counts. Decreased expression of striatal gene markers are detected in heterozygous mice from ~4.5 months of age (Heikkinen et al, 2012; Menalled et al, 2012; Smith et al, 2014). In addition to these behavioral and pathological phenotypes, zQ175 KI mice also have electrophysiological, histological, and metabolic alterations (Heikkinen et al, 2012; Menalled et al, 2012; Plotkin et al, 2014; Smith et al, 2014; Tong et al, 2014), which suggest it as a robust mouse model to study molecular mechanisms and therapeutic interventions of HD.…”

Using Drosophila models of Huntington's disease as a translatable tool

“…The most recent KI mouse model, Q175, more closely recapitulates the human disease, as multiple phenotypes can be observed in the heterozygous condition (Smith et al, 2014).…”

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

“…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.…”