Identifying phenotypic change across time in mouse models of Down syndrome
Shaw, Patricia Rein
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Advances in Down syndrome (DS) research depend on the availability of mouse models that replicate the genetic landscape and resulting phenotypes of DS which allow for experimental manipulation to correlate cellular and molecular changes with behavior, in a way that is not possible with human studies alone. These models have been a critical component in understanding the underlying mechanism of the intellectual disability in people with Down syndrome. The Ts(1716)65Dn (Ts65Dn) mouse is one of the most commonly used models as it recapitulates many of the phenotypes seen in individuals with Down syndrome, including neuroanatomical changes and impaired learning and memory. Although Ts65Dn exhibits a number of traits also present in DS, studies have produced variable results across time that call into question the validity of Ts65Dn and its use as a tool for studying Down syndrome. As Ts65Dn is the platform employed to gather preclinical evidence for treatments of DS, a critical assessment regarding the validity of the model over time is necessary. In this study, we conduct a rigorous and comprehensive, comparative analysis of multiple cohorts from the Ts65Dn line to assess the stability and reproducibility of neuroanatomical and behavioral characteristics. We measured gross anatomical brain and body size, neuronal density in the hippocampus and cerebellum, alterations to oligodendrocyte maturation and myelination, acquisition of developmental milestones, and learning and memory performance using the Morris water maze. Our results show a significant amount of variability in Ts65Dn, both across as well as within cohorts. Inconsistent phenotypes in Ts65Dn mice highlight specific cautions and caveats for use of these mice when studying Down syndrome and suggest it is not always the most appropriate model system to use. In addition to phenotypic variability, a major pitfall of the Ts65Dn model is the unintended triplication of 60 non-DS-related genes and the unknown consequences on resulting phenotypes. Recent advances in gene editing strategies have allowed for the gene dosage normalization of those 60 genes and the generation of a new mouse model of Down syndrome, Ts66YAH. As this newly developed line has not yet been characterized, we conducted an analysis complimentary to our study of Ts65Dn to investigate the utility of Ts66YAH for Down syndrome research. We found Ts66YAH mice show no measurable neuroanatomical changes, developmental delays, or learning and memory deficits suggesting that the deleted non-DS-related genes do influence the phenotypes seen in Ts65Dn. Although Ts66YAH is a more genetically representative model of Down syndrome compared to Ts65Dn, it does not exhibit disease relevant phenotypes and therefore, may not be a suitable model for studying DS. The various downfalls identified in the present study may be impacting other mouse models of DS as well and thus, our analysis of Ts65Dn across time and comparative study of Ts66YAH illustrate the need for careful use and increased rigor to ensure translational and reproducible results when working with all mouse models of Down syndrome.
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