Research reportLongitudinal analysis of the behavioural phenotype in YAC128 (C57BL/6J) Huntington's disease transgenic mice
Introduction
Huntington's disease is a genetically inherited neurodegenerative disorder with 100% penetrance, caused by a mutation in the HTT gene [10], the gene responsible for the protein huntingtin (Htt). The mutation causes the pathological expansion of the polyQ region in exon 1 of the gene resulting in widespread atrophy and cell death in the brain through unknown mechanisms [8]. Cell death is largely concentrated on the medium spiny neurons (MSNs) of the striatum where there is a relative sparing of the large cholinergic inter-neurons, but cortical areas also demonstrate marked cell death with cortical thinning and sulcal widening being a feature of the cortical atrophy [2], [14], [25], [26], [32]. The most prominent marker of cellular pathology is the formation of protein aggregates created from cleaved, insoluble, N-terminal fragments of the mutant protein and other sequestered proteins. Aggregates may ultimately form dense neuronal intra-nuclear inclusions (NIIs) [4]. At present the role of the aggregation process and the NIIs in neurodegeneration is unknown. In functional terms, the neuropathology induces a broad spectrum of behavioural changes beginning with subtle cognitive and emotional changes [5], [11], [31] and including highly specific learning deficits in for example, implicit learning [12] and set-shifting tasks [15], [16], [17] prior to the manifestation of motor abnormalities and choreic movements that characterise the disorder.
Since the disease is caused by a single mutation it lends itself readily to recapitulation in the form of mouse models of the disease, of which several have been created [7], [18], [19], [22], [24], [28], [37]. The YAC128 mouse is a transgenic model of HD where the transgene carrying a construct with 128 CAG repeats [30] was introduced via a yeast artificial chromosome. The original model, which was bred on an FVB/N background strain, recapitulates several aspects of disease including the neuropathological features of striatal and cortical cell loss, protein aggregation and NIIs [9], [30], [34], as well as motor and cognitive deficits [30], [33], [34], [35], [36].
The motor deficits are apparent from an early age in the FVB variant of the YAC128. Motor abnormalities include deficits in motor learning and coordination as measured by the accelerating rotarod [33], [34], [35], [36] and initial hyperactivity is followed by a general reduction in movement in open field activity assessments [30], [35]. The hyperactivity appears at 3 months of age, with the rotarod acquisition deficits appearing around 2 months of age [36], and performance on a fixed speed rotarod correlated highly with the striatal neuronal loss at 6, 9 and 12 months of age [30]. Several cognitive deficits have been described. The YAC128 mice were slower to habituate to an open field arena at 8 months of age, and learning deficits where the time taken to swim, and the number of errors incurred, in free-swimming water T-maze tests were greater for the YAC128s than their wildtype littermates at 8.5 months of age [36]. A decreased prepulse inhibition was present by 12 months [36].
Whilst the YAC128 on the FVB background is essentially a good recapitulation of the human condition, the major drawback is that the background strain confers a pronounced retinal degeneration to the model which limits the range of tasks that the animals can perform. However, the YAC128 mouse has been crossed on a C57BL/6J making it ideally suited for behavioural testing [21], [33], although on this background strain the disease has been found to be more resistant to the disease than the original FVB line [33]. Nevertheless, motor deficits are present from an early age (4 months), and age where striatal volume is reduced but no cell loss is present [33]. To date relatively little work has been conducted on the C57BL/6J variant of the YAC128 mouse.
The aim of the present paper was to characterise the nature and evolution of behavioural deficits in the C57BL/6J YAC128 mouse line to determine whether this model is a good representation of the human condition on which to base therapeutic trials. The study was run through the longitudinal application (2–24 months of age) of a number of assessments (bodyweight, rotarod, balance beam, prepulse inhibition and acoustic startle, and a variation of the Morris water maze test), with which to gauge the relative contributions to the disease of specific motor and cognitive deficits.
Section snippets
Subjects
In total 100 mice were used in the experiment, 53 wildtypes (21 females and 32 males), and 47 YAC128 hemizygote transgene carriers (26 females and 21 males). The founders of the original YAC128 colony were bred on a FVB/N background at the Hayden laboratory (University of British Columbia, Vancouver, Canada) where C57BL/6/J background was introduced as a separate mouse line. The founders from our colony are derived from this mouse line which has a yeast artificial chromosome containing human
Body weight
When grouped by genotype there was no difference in body weights (Fig. 1A) between the wildtype and their YAC128 transgenic littermates (p > 0.05, n.s.), but there was a clear sex difference between the mice with the males being heavier than females (F1,65 = 165.52, p < 0.001). This did not differ by genotype (p > 0.05, n.s.), until age was factored into the analyses whereby a significant 3-way interaction effect was found (F21,698 = 4.64, p < 0.001). This age-related effect was due to an initial (4–14
Discussion
The presented data demonstrate a disease profile in the YAC128 carrier mice that is characterised by motor and cognitive deficits. Body weight increased abnormally in the male YAC128 mice compared with their wildtype littermates over the initial 10 months of life in agreement with a previous study in the same mouse line [21]. In the latter study, the weight of the male carrier mice remained higher throughout the life of the animal, in contrast to the present study where weight stabilised to
Conflicts of interest
The authors have no conflicts of interest to declare.
Acknowledgments
This work was funded by the Cure Huntington's Disease Initiative (CHDI). We would like to thank Ali Baird and Lyn Elliston for their technical support.
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