Environmental enrichment slows disease progression in R6/2 Huntington's disease mice

Hockly, Emma; Cordery, Patricia M.; Woodman, Benjamin; Mahal, Amarbirpal; Dellen, Anton van; Blakemore, Colin; Lewis, Cathryn M.; Hannan, Anthony J.; Bates, Gillian P.

doi:10.1002/ana.10094

Cited by 305 publications

(190 citation statements)

References 34 publications

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“…However, questions arise regarding the differences in phenotype between the shortstop and the R6͞2 short fragment mouse model. The R6͞2 model expresses the first exon of htt with 144 (17) to 205 (27) polyQ repeats (compared with 120Q in the shortstop) and demonstrates rotarod deficits (28), nonselective brain weight decreases, and an early death phenotype (17). It is surprising that shortstop and R6͞2 mice share no phenotypic features.…”

Section: Discussionmentioning

confidence: 99%

Absence of behavioral abnormalities and neurodegenerationin vivodespite widespread neuronal huntingtin inclusions

Slow

Graham

Osmand

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

254

201

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We have serendipitously established a mouse that expresses an N-terminal human huntingtin (htt) fragment with an expanded polyglutamine repeat (Ϸ120) under the control of the endogenous human promoter (shortstop). Frequent and widespread htt inclusions occur early in shortstop mice. Despite these inclusions, shortstop mice display no clinical evidence of neuronal dysfunction and no neuronal degeneration as determined by brain weight, striatal volume, and striatal neuronal count. These results indicate that htt inclusions are not pathogenic in vivo. In contrast, the full-length yeast artificial chromosome (YAC) 128 model with the identical polyglutamine length and same level of transgenic protein expression as the shortstop demonstrates significant neuronal dysfunction and loss. In contrast to the YAC128 mouse, which demonstrates enhanced susceptibility to excitotoxic death, the shortstop mouse is protected from excitotoxicity, providing in vivo evidence suggesting that neurodegeneration in Huntington disease is mediated by excitotoxic mechanisms.Huntington disease ͉ mouse models ͉ excitotoxicity ͉ aggregates ͉ fragment H untingtin (htt), the protein product encoded by the gene mutated in Huntington disease (HD), forms aggregates and inclusion bodies in the presence of a pathogenic expanded polyglutamine (polyQ) repeat. Htt protein inclusions are a hallmark of HD and are present in brains of human patients (1), in HD mouse models (2, 3), and in cell culture models of HD (4). It is still controversial whether htt inclusions are pathogenic (2), benign biomarkers (5), or neuroprotective (4, 6). The distinction between these hypotheses is clinically relevant, because much therapeutic research has focused on screening compounds for their ability to inhibit inclusion formation (7,8). A decrease in inclusion formation has been interpreted as a positive outcome in preclinical therapeutic trials with mouse models (9, 10).Increasing evidence in vitro in cell culture models supports the hypothesis that htt inclusions are not pathogenic (5, 11). In a recent study, Arrasate et al. (4) discovered that in their cell culture system, neurons with inclusions had an increased likelihood of survival compared with neurons without inclusions. However, because these results were obtained in a cell culture system, the question of whether htt inclusions are toxic in vivo during the lifespan of an organism and therefore clinically relevant for patients with HD remains unanswered.Examinations of inclusions in brains from HD patients are limited due to the inability to sample inclusions over the natural history of the disease, and, therefore, studies of mouse models of HD can be useful in determining the role of htt inclusions in vivo. The yeast artificial chromosome (YAC) 128 model of HD, which expresses full-length mutant htt, forms intranuclear inclusions 12 months after the onset of behavioral changes measured by rotarod and 6 months after striatal neuronal degeneration (3).During the development of the full-length YAC mouse models, a m...

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Section: Discussionmentioning

confidence: 99%

Absence of behavioral abnormalities and neurodegenerationin vivodespite widespread neuronal huntingtin inclusions

Slow

Graham

Osmand

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

254

201

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“…Currently, it is not known whether expression of the GH transgene used in these studies is modified by environmental conditions. For transgenic mice strains, environmental enrichment can provide morphological compensation in the brain for the effects caused by a transgene (44)(45)(46). In general, environmental complexity reduces hormonal effects on behavior (47), and GH treatment of nontransgenic brown trout (Salmo trutta) had stronger phenotypic effects in the hatchery than under natural conditions (48).…”

Section: Discussionmentioning

confidence: 99%

Gene–environment interactions influence ecological consequences of transgenic animals

Sundström

Lõhmus

Tymchuk

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Production of transgenic animals has raised concern regarding their potential ecological impact should they escape or be released to the natural environment. This concern has arisen mainly from research on laboratory-reared animals and theoretical modeling exercises. In this study, we used biocontained naturalized stream environments and conventional hatchery environments to show that differences in phenotype between transgenic and wild genotypes depend on rearing conditions and, critically, that such genotype-by-environment interactions may influence subsequent ecological effects in nature. Genetically wild and growth hormone transgenic coho salmon (Oncorhynchus kisutch) were reared from the fry stage under either standard hatchery conditions or under naturalized stream conditions. When reared under standard hatchery conditions, the transgenic fish grew almost three times longer than wild conspecifics and had (under simulated natural conditions) stronger predation effects on prey than wild genotypes (even after compensation for size differences). In contrast, when fish were reared under naturalized stream conditions, transgenic fish were only 20% longer than the wild fish, and the magnitude of difference in relative predation effects was much reduced. These data show that genotype-by-environment interactions can influence the relative phenotype of transgenic and wild-type organisms and that extrapolations of ecological consequences from phenotypes developed in the unnatural laboratory environment may lead to an overestimation or underestimation of ecological risk. Thus, for transgenic organisms that may not be released to nature, the establishment of a range of highly naturalized environments will be critical for acquiring reliable experimental data to be used in risk assessments.coho salmon ͉ phenotypic plasticity ͉ risk-assessment

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“…Two independent groups have analyzed the effect of an increased environmental stimulation on the phenotype and neuropathology of R6 mice van Dellen et al, 2000;Hockly et al, 2002;Glass et al, 2004;Spires et al, 2004). These studies have demonstrated that the exposure of R6/1 (van Dellen et al, 2000;Glass et al, 2004;Spires et al, 2004) or R6/2 (Hockly et al, 2002) mice to an enriched environment (consisting of large standard cages with cardboard, paper and plastic objects, which were changed every two to three times per week) delayed the onset of motor symptoms, decreased the severity of the clasping phenotype, and reduced the loss of the peristriatal cerebral volume. Carter et al (2000) also demonstrated that, improving the access to food and water had beneficial effects.…”

Section: Environmental Enrichmentmentioning

confidence: 99%

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Gil

Rego

2009

Brain Research Reviews

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

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Environmental enrichment slows disease progression in R6/2 Huntington's disease mice

Cited by 305 publications

References 34 publications

Absence of behavioral abnormalities and neurodegenerationin vivodespite widespread neuronal huntingtin inclusions

Absence of behavioral abnormalities and neurodegenerationin vivodespite widespread neuronal huntingtin inclusions

Gene–environment interactions influence ecological consequences of transgenic animals

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

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