Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice

Roubertoux, Pierre L.; Baril, Nathalie; Cau, Pierre; Scajola, Christophe; Ghata, Adeline; Bartoli, Catherine; Bourgeois, P.; Christofaro, Julie di; Tordjman, Sylvie; Carlier, Michèle

doi:10.1007/s10519-017-9835-5

Cited by 19 publications

(16 citation statements)

References 89 publications

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“…We calculated the median value of the four trials for the seven blocks. The between‐block difference defined the learning slope 9 . We used Statistical Package for the Social Sciences (v19).…”

Section: Methodsmentioning

confidence: 99%

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

et al. 2020

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractObjective: Early onset epileptic encephalopathy with suppression-burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage-dependent potassium channel subunit, leading to so-called KCNQ2related epileptic encephalopathy (KCNQ2-REE). To study the pathophysiology of KCNQ2-REE in detail and to provide a relevant preclinical model, we generated and described a knock-in mouse model carrying the recurrent p.(Thr274Met) variant. Methods: We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre-deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests. Results: The Kcnq2 Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2 Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2 Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development. | 869 MILH et aL.

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Section: Methodsmentioning

confidence: 99%

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

et al. 2020

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“…Redrawn from Amendola et al (2004). the other strains (Roubertoux et al, 2017). Newborns carrying a mutation resulting in an amyotrophic lateral sclerosis model were subjected to an abbreviated test battery (Fig.…”

Section: Anticipated Resultsmentioning

confidence: 99%

“…Figure shows that the mice with the 152F7 extra fragment were more generally impacted, but that the three other trisomic strains were not healthy (Roubertoux et al., ). As expected from these results, we observed in adults a large effect size of impairment of forepaw strength and of hind paw incoordination with 152F7, and an effect in the other strains (Roubertoux et al., ). Newborns carrying a mutation resulting in an amyotrophic lateral sclerosis model were subjected to an abbreviated test battery (Fig.…”

Section: Commentarymentioning

confidence: 99%

Measuring Preweaning Sensorial and Motor Development in the Mouse

2018

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The immaturity at birth and the slowness of ontogenic processes in mice provide the opportunity to measure rates of development. We describe here 18 measures covering the sensorial and motor onset from birth to weaning. The measures are non-invasive, making a follow-up strategy possible. The first basic protocol indicates how to produce mice with known conceptional or chronological age, as the control of the age is a prerequisite to compare rates of development in groups of mice. The second basic protocol describes a set of methods for identifying the pups during a follow-up study. A third basic protocol describes testing newborn mice for the appearance of sensorial and motor abilities in a follow-up design. Taken together, the three protocols make possible the validation of potential murine models of interest for understanding human developmental disorders. © 2018 by John Wiley & Sons, Inc.

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“…[193][194][195][196][197][198][199][200][201][202][203][204][205][206][207][208] Yet, thorough analyses of all the different trisomic mouse models are still underway, and results are not consistent among models. 142,145,196,204,209 Importantly, the different mouse models have differing or no phenotypes that might link to DS disease characteristics. 210 Although the behavioral phenotypes of some of the DS mouse models could be reminiscent of cognitive characteristics of DS-affected individuals, structural and molecular mechanisms that underlie the phenotypes are different.…”

Section: Modeling Neurological Symptoms and Behavioral Deficitsmentioning

confidence: 99%

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

Zhao

Bhattacharyya

2018

The American Journal of Human Genetics

131

103

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The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Human pluripotent stem cells have emerged as a much-needed model system for investigating human-specific biology and disease mechanisms. However, questions remain regarding whether these cell-culture-based models are sufficient or even necessary. In this review, we summarize human-specific features of neurodevelopment and the most common neurodevelopmental disorders, present discrepancies between animal models and human diseases, demonstrate how human stem cell models can provide meaningful information, and discuss the challenges that exist in our pursuit to understand distinctively human aspects of neurodevelopment and brain disease. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or animal, to mimic disease characteristics.

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Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice

Cited by 19 publications

References 89 publications

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

Measuring Preweaning Sensorial and Motor Development in the Mouse

Human Models Are Needed for Studying Human Neurodevelopmental Disorders

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