Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome

Abstract

Mouse models of Down syndrome (DS) have been invaluable tools for advancing knowledge of the underlying mechanisms of intellectual disability in people with DS. 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 DS, including neuroanatomical changes and impaired learning and memory. In this study, we utilize rigorous metrics to evaluate multiple cohorts of Ts65Dn ranging from 2014 to the present, including a stock of animals recovered from embryos frozen within ten generations after the colony was first created in 1990. Through quantification of pre- and post-natal brain development and several behavioral tasks, our results provide a comprehensive comparison of Ts65Dn across time and show a significant amount of variability both across cohorts as well as within cohorts. The inconsistent phenotypes in Ts65Dn mice highlight specific cautions and caveats for use of this model. We outline important steps for ensuring responsible use of Ts65Dn in future research.

Time-dependent diffusion MRI probes cerebellar microstructural alterations in a mouse model of Down syndrome

“…Other than creating better genetic models of trisomy 21, it is also critical to standardize and upgrade methods for analysing DS phenotypes. A recent study 71 suggests that phenotypic drift in neuroanatomical and behavioural analyses exist in Ts65Dn after comparing different cohorts from two Ts65Dn strains, Ts65Dn 1924 (C57BL/6JEiJ × C3Sn with mutated Pde6b, Jax 001924) and Ts65Dn 5252 (C57BL/6JEiJ × C3Sn with wildtype Pde6b, Jax 005252). Although many prenatal and postnatal phenotypes are not stable, the most critical phenotype—‘learning and memory deficits in MWM’ of the current cohort ‘5252 Cryo2010 ’, is still consistent with the original MWM finding 40 and their earlier MWM finding, 72 and it also should be pointed out that the design of MWM is strongly correlated with the sensitivity.…”

Multimodal in vivo Imaging of the Integrated Postnatal Development of Brain and Skull and Its Co-modulation With Neurodevelopment in a Down Syndrome Mouse Model

“…Mice were genotyped at PD14 by PCR from ear snips adapting the protocol in Shaw et al (34). Trisomic primers, Chr17fwd- Treatment was randomized by treating half of the litters.…”

Building the Future Therapies for Down Syndrome: The Third International Conference of the T21 Research Society

“…His lab's findings illustrate that even animals of the same trisomic line bred on the same background but of different historic times and generation exhibit significant variation in well-documented phenotypes, including cortical expansion during embryonic development, the trajectory of oligodendrogenesis and maturation, and learning and memory performance. Dr. Haydar's work suggests there may be a greater degree of variability than previously anticipated and that the phenotypes of trisomic animals may not be preserved from generation to generation (Shaw et al 2020) and raises the idea that variability between animals may be a representation of the variability within the DS population.…”

“…The phenotypes also showed a drift in wild type mice. Dr. Haydar's work suggests there may be a greater degree of variability than previously anticipated and that the phenotypes of trisomic animals may not be preserved from generation to generation [Shaw et al, 2020] and raises the idea that variability between animals may be a representation of the variability within the DS population.…”