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

Plank, Anne-Christine; Canneva, Fabio; Raber, Kerstin; Urbach, Yvonne K.; Dobner, Julia; Puchades, Maja; Bjaalie, Jan G.; Gillmann, Clarissa; Bäuerle, Tobias; Rieß, Olaf; Nguyen, Hoa Huu Phuc; Hörsten, Stephan von

doi:10.3389/fnins.2018.00011

Cited by 6 publications

(19 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The knockin mouse showed appeared normal up to 6 months, but was not characterised past that age. Two lines of transgenic (tg) HD rat have also been generated, that carry a CAG repeat of 51 (SPRDTgHD 34 and F344tgHD 35 ). Both HD rat lines show Htt-positive aggregate pathology by 21 months, particularly those regions associated with regulation of emotion (nucleus accumbens, amygdala), although up to 21 months neither strain show strong cortical staining and both show significant hippocampal staining 34,35 .…”

Section: Discussionmentioning

confidence: 99%

“…Two lines of transgenic (tg) HD rat have also been generated, that carry a CAG repeat of 51 (SPRDTgHD 34 and F344tgHD 35 ). Both HD rat lines show Htt-positive aggregate pathology by 21 months, particularly those regions associated with regulation of emotion (nucleus accumbens, amygdala), although up to 21 months neither strain show strong cortical staining and both show significant hippocampal staining 34,35 . Clearly, differences in transgene construct, promoter and expression levels and species differences, as well as different antibodies used for visualisation of brain pathology make direct comparisons of these lines of HD rodent models with the R6/2_50 mouse inadvisable.…”

Section: Discussionmentioning

confidence: 99%

“…As with the R6/2_50 mice, the tgHD rat cognitive phenotype evolution is complex, with both improved and worsening phenotypes being measurable compared to WT rats. It is nevertheless intriguing to note that at an early age, both lines of tgHD rats are more social and less anxious than WT rats 35,36 and the performance of young SPRDTgHD rats on the rotarod is better than that of the WT controls 36 . SPRDTgHD rats also showed better learning and reacquisition of discriminative fear conditioning 37 .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington’s disease

Morton

Skillings

Wood

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Antagonist pleiotropy, where a gene exerts a beneficial effect at early stages and a deleterious effect later on in an animal’s life, may explain the evolutionary persistence of devastating genetic diseases such as Huntington’s disease (HD). To date, however, there is little direct experimental evidence to support this theory. Here, we studied a transgenic mouse carrying the HD mutation with a repeat of 50 CAGs (R6/2_50) that is within the pathological range of repeats causing adult-onset disease in humans. R6/2_50 mice develop characteristic HD brain aggregate pathology, with aggregates appearing predominantly in the striatum and cortex. However, they show few signs of disease in their lifetime. On the contrary, R6/2_50 mice appear to benefit from carrying the mutation. They have extended lifespans compared to wildtype (WT) mice, and male mice show enhanced fecundity. Furthermore, R6/2_50 mice outperform WT mice on the rotarod and show equal or better performance in the two choice discrimination task than WT mice. This novel mouse line provides direct experimental evidence that, although the HD mutation causes a fatal neurodegenerative disorder, there may be premorbid benefits of carrying the mutation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington’s disease

Morton

Skillings

Wood

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Activity of animals was recorded. Parameters such as, 1) the time needed to enter the "center" zone for the first time, 2) the time spent in the "center" zone, 3) the frequency and duration of rearing behavior, and 4) the frequency and duration of grooming behavior were measured manually 4,24,60 . The moment when both forepaws crossed the imaginary line was counted as enter the "center zone".…”

Section: Monitoring Of Mental and Cognitive Functions Following Gmh mentioning

confidence: 99%

Serelaxin activates eNOS, suppresses inflammation, attenuates developmental delay and improves cognitive functions of neonatal rats after germinal matrix hemorrhage

Seyler

Bäuerle

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMHmediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U). Seven day old Sprague-Dawley rat pups (P7) were used (n = 63). GMH animals were divided in vehicle or serelaxin treated (3 µg once, 30 µg once, 30 µg multiple, i.p., starting 30 after GMH and then daily). Sham operated animals were used. We monitored the developmental profile working memory and spatial function (T-maze and open field test respectively). At day 28, all rats underwent MRI-scans for assessment of changes in cortical thickness and white matter loss. Effects of Serelaxin on eNOS pathway activation and post-GMH inflammation were evaluated. We demonstrated that Serelaxin dose-dependently attenuated GMH-induced developmental delay, protected brain and improved cognitive functions of rats after GMH. That was associated with the decreased post-GMH inflammation, mediated at least partly by amelioration of GMH-induced eNOS inhibition.

show abstract

“…It constitutes a backcrossed version of the thoroughly characterized SPRDtgHD model ( von Hörsten et al, 2003 ) with a truncated Htt construct comprising 51 CAG repeat. Homozygous males have been shown to reflect major key symptoms of human HD pathology like striatal volume reduction at 21 months and an early behavioral phenotype ( Plank et al, 2018 ). A comprehensive sex comparison of this model as well as in-depth analysis of potential gene-dosage (zygosity) effects and advanced investigations into motor deficits as well as early, prodromal-like symptoms are still owing ( Plank et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Gene-dosage- and sex-dependent differences in the prodromal-Like phase of the F344tgHD rat model for Huntington disease

Ratz-Wirsching,

Habermeyer,

Moceri

et al. 2024

Front. Neurosci.

Self Cite

View full text Add to dashboard Cite

In Huntington disease (HD) the prodromal phase has been increasingly investigated and is currently in focus for early interventional treatments. Also, the influence of sex on disease progression and severity in patients is under discussion, as a sex-specific impact has been reported in transgenic rodent models for HD. To this end, we have been studying these aspects in Sprague Dawley rats transgenic for HD. Here, we took up on the congenic F344tgHD rat model, expressing a fragmented Htt construct with 51 CAG repeats on an inbred F344 rat background and characterized potential sexual dimorphism and gene-dosage effects in rats during the pre-symptomatic phase (1–8 months of age). Our study comprises a longitudinal phenotyping of motor function, emotion and sensorimotor gating, as well as screening of metabolic parameters with classical and automated assays in combination with investigation of molecular HD hallmarks (striatal cell number and volume estimation, appearance of HTT aggregates). Differences between sexes became apparent during middle age, particularly in the motor and sensorimotor domains. Female individuals were generally more active, demonstrated different gait characteristics than males and less anxiolytic-like behavior. Alterations in both the time course and affected behavioral domains varied between male and female F344tgHD rats. First subtle behavioral anomalies were detected in transgenic F344tgHD rats prior to striatal MSN cell loss, revealing a prodromal-like phase in this model. Our findings demonstrate that the congenic F344tgHD rat model shows high face-validity, closely resembling the human disease’s temporal progression, while having a relatively low number of CAG repeats, a slowly progressing pathology with a prodromal-like phase and a comparatively subtle phenotype. By differentiating the sexes regarding HD-related changes and characterizing the prodromal-like phase in this model, these findings provide a foundation for future treatment studies.

show abstract

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

Cited by 6 publications

References 40 publications

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington’s disease

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington’s disease

Serelaxin activates eNOS, suppresses inflammation, attenuates developmental delay and improves cognitive functions of neonatal rats after germinal matrix hemorrhage

Gene-dosage- and sex-dependent differences in the prodromal-Like phase of the F344tgHD rat model for Huntington disease

Contact Info

Product

Resources

About