Transgenic Rat Models of Huntington’s Disease

Casaca-Carreira, João; Jahanshahi, Ali; Zeef, Dagmar H.; Kocabıcak, Ersoy; Vlamings, Rinske; Hörsten, Stephan von; Temel, Yasin

doi:10.1007/7854_2013_245

Cited by 18 publications

(10 citation statements)

References 29 publications

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“…Interestingly, reduction in stride length, which is considered as a hypokinetic feature, can be found at later ages, showing that gait follows the hyperkinetic and hypokinetic course of the disease in HD [ 7 ]. Of note, the phenotype of the tgHD rats comprises an early symptomatic phase, characterized by hypermobility and a late disease phase, where hypokinesia is the dominant symptom [ 18 , 19 , 25 ], resembling the human condition.…”

Section: Discussionmentioning

confidence: 99%

“…The discovery of the HD gene in 1993 [ 1 ] facilitated the development of several genetically modified rodent models that mimic the onset and progression of the disease. Among those, transgenic rat model of HD (tgHD) has widely been used [ 17 ] and presents typical neuropathological, neurophysiological, and behavioral features resembling the human condition [ 18 , 19 ]. The tgHD is the only described experimental model of HD exhibiting choreiform movements [ 9 , 17 , 18 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Among those, transgenic rat model of HD (tgHD) has widely been used [ 17 ] and presents typical neuropathological, neurophysiological, and behavioral features resembling the human condition [ 18 , 19 ]. The tgHD is the only described experimental model of HD exhibiting choreiform movements [ 9 , 17 , 18 , 20 ]. The onset of hyperkinetic movements is at the ages of 6-8 months, which might differ from one colony to another, and its severity increases with disease progression [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Coexistence of Gait Disturbances and Chorea in Experimental Huntington’s Disease

Casaca-Carreira

Temel

Zelst

et al. 2015

Behavioural Neurology

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. The clinical features are progressive motor dysfunction, cognitive deterioration, and psychiatric disturbances. Unpredictable choreic movements, among the most characteristic hallmarks, may contribute to gait disturbances and loss of balance in HD individuals. In this study, we aimed to investigate and characterize the gait abnormalities and choreic movements in a transgenic rat model of HD (tgHD). TgHD presents typical neuropathological, neurophysiological, and behavioral aspects mimicking some of the key features of human HD and is the only described experimental model for HD that exhibits choreiform movements. We used the Catwalk, with emphasis on static and dynamic gait parameters, to test the hypothesis that at symptomatic age (9 months) the dynamic measures of gait in HD are altered and coexist with choreiform movements. Our results showed that the dynamic parameters seem to be more affected than static parameters at this age in tgHD rats. The number of steps and step cycles and swing speed of the paws were increased in tgHD rat in comparison to wild-type controls. Our study demonstrates that gait abnormalities coexist with chorea rather than being caused by it. These symptoms may originate from distinct networks in the basal ganglia and downstream connections.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Coexistence of Gait Disturbances and Chorea in Experimental Huntington’s Disease

Casaca-Carreira

Temel

Zelst

et al. 2015

Behavioural Neurology

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“…Diverse genetically engineered mouse models provide a valuable tool for neuropathological, behavioral and experimental therapeutic studies (for review see Pouladi et al, 2013 ). However, modeling neurodegenerative disorders in Rattus norvegicus offers several advantages, such as higher similarity of rat and human brain organization, convenient imaging and surgery due to larger size, and more complex behavioral phenotypes (Urbach et al, 2010 ; Carreira et al, 2015 ). For instance, more sophisticated behavioral tests of learning and memory can be applied in this species compared to mouse.…”

Section: Introductionmentioning

confidence: 99%

Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease

Plank¹,

Canneva²,

Raber³

et al. 2018

Front. Neurosci.

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The transgenic rat model of Huntington disease expressing a fragment of mutant HTT (tgHD rat) has been thoroughly characterized and reproduces hallmark symptoms of human adult-onset HD. Pursuing the optimization of this model for evaluation of translational therapeutic approaches, the F344 inbred rat strain was considered as advantageous genetic background for the expression of the HD transgenic construct. In the present study, a novel congenic line of the SPRDtgHD transgenic model of HD, carrying 51 CAG repeats, was generated on the F344 rat genetic background. To assess the behavioral phenotype, classical assays investigating motor function, emotion, and sensorimotor gating were applied, along with automated screening of metabolic and activity parameters as well as operant conditioning tasks. The neuropathological phenotype was analyzed by immunohistochemistry and ex vivo magnetic resonance imaging. F344tgHD rats displayed markedly reduced anxiety-like behavior in the social interaction test and elevated impulsivity traits already at 3 months of age. Neuropathologically, reduced striatal volume and pronounced aggregation of mutant huntingtin in several brain regions were detected at later disease stage. In conclusion, the congenic F344tgHD model reproduces key aspects of the human HD phenotype, substantiating its value for translational therapeutic approaches.Keywords: Huntington disease, transgenic rat model, F344 rat, behavioral phenotyping, operant conditioning, huntingtin aggregates Plank et al. F344tgHD Rat Model of HD

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“…Although the adult rat brain is only about four times larger than a mouse brain (about 2 g vs. 0.5 g), rats are generally thought to be smarter and capable of performing more difficult cognitive tasks [71]. Deficiencies with other mouse models of CNS disorders have also prompted the neuroscience research community to pursue the development of rat disease models, for example Huntington’s Disease, Rett Syndrome, and Parkinson’s Disease [72,73,74].…”

Section: The Pathway From Preclinical Experimentation To a Clinicamentioning

confidence: 99%

The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome

2019

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Viral vector-mediated gene therapy has grown by leaps and bounds over the past several years. Although the reasons for this progress are varied, a deeper understanding of the basic biology of the viruses, the identification of new and improved versions of viral vectors, and simply the vast experience gained by extensive testing in both animal models of disease and in clinical trials, have been key factors. Several studies have investigated the efficacy of adeno-associated viral (AAV) vectors in the mouse model of fragile X syndrome where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. These studies have demonstrated a range of efficacies in different tests from full correction, to partial rescue, to no effect. Here we provide a backdrop of recent advances in AAV gene therapy as applied to central nervous system disorders, outline the salient features of the fragile X studies, and discuss several key issues for moving forward. Collectively, the findings to date from the mouse studies on fragile X syndrome, and data from clinical trials testing AAVs in other neurological conditions, indicate that AAV-mediated gene therapy could be a viable strategy for treating fragile X syndrome.

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Transgenic Rat Models of Huntington’s Disease

Cited by 18 publications

References 29 publications

Coexistence of Gait Disturbances and Chorea in Experimental Huntington’s Disease

Coexistence of Gait Disturbances and Chorea in Experimental Huntington’s Disease

Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease

The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome

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