Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of down syndrome.
Open accessAbstract
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 use 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 2010. Through quantification of prenatal and postnatal 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. This article has an associated First Person interview with the first author of the paper.
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In Ts65Dn, the number of actively proliferating cells in the germinal zone of the dorsal telencephalon is decreased and this deficit persists postnatally, with fewer proliferating cells being found in the hippocampus.
“In concert, the number of actively proliferating cells in the germinal zone of the dorsal telencephalon is decreased (Aziz et al., 2018; Shaw et al., 2020) and this deficit persists postnatally, with fewer proliferating cells being found in the hippocampus (Contestabile et al., 2007).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Shaw et al., 2020
The Results section (‘Cellular changes underlying the 5252Cryo2010 pallial thickness phenotype’; page unavailable) reports fewer mitotic cells in the subventricular zone of 5252Cryo2010 Ts65Dn embryos at E13.5. It also reports increased mitotic cells in that zone in a different Ts65Dn cohort at later embryonic ages, so the unqualified statement about Ts65Dn overgeneralizes the finding. The postnatal hippocampal clause is attributed to Contestabile et al., not Shaw et al., and is not assessed here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn a recent comparison of cohorts of Ts65Dn animals spanning from 2010 to 2019, neither decreases in neuronal density in the cerebellum or hippocampus nor embryonic cortical size differences were measured.
“In a recent comparison of cohorts of Ts65Dn animals spanning from 2010 to 2019, neither decreases in neuronal density in the cerebellum or hippocampus nor embryonic cortical size differences were measured (Shaw et al., 2020).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Shaw et al., 2020
The Results section, “Hippocampal and cerebellar cell densities” (page not provided), reports no decreased neuronal density in the three cohorts studied. But “Embryonic gross anatomical measurements” and “Embryonic pallial thickness measurements” report significant cortical size differences in some cohorts, including reduced pallial thickness in 5252Cryo2010 embryos. The claim’s assertion about embryonic cortical size differences is therefore not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMany phenotypes described in Ts65Dn are susceptible to phenotypic drift and are variable between cohorts.
“However, many of the phenotypes that have been described in Ts65Dn have recently been found to be susceptible to phenotypic drift and are variable between cohorts (Shaw et al., 2020).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Shaw et al., 2020
These recapitulated phenotypes appear to be subject to phenotypic drift.
“However, these recapitulated phenotypes appear to be subject to phenotypic drift.”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Shaw et al., 2020
Behaviorally, Ts65Dn appears to capture many of the features of Down syndrome including developmental delays and learning and memory deficits.
“Behaviorally, Ts65Dn appears to capture many of the features of DS including developmental delays and learning and memory deficits (Reeves et al., 1995; Olmos-Serrano et al., 2016b; Shaw et al., 2020).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Shaw et al., 2020
Ts65Dn historically recapitulated some known phenotypes (volumetric changes during development, neuronal hypocellularity, changes in proliferation) but lately these phenotypes have been subject to phenotypic drift and unpredictable variability.
“Ts65Dn historically has recapitulated some of the known phenotypes (volumetric changes during development, neuronal hypocellularity, and changes in proliferation) but lately these phenotypes have been subject to phenotypic drift and unpredictable variability making it difficult to use this model in an effective manner (Shaw et al., 2020).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Shaw et al., 2020
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Ultrasonic vocalization phenotypes in the Ts65Dn and Dp(16)1Yey mouse models of Down syndrome
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Vertebrate and Invertebrate Animal Models for the Study of Down Syndrome
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Characterization of Apathy-Like Behaviors in Mouse Models of Down Syndrome
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Increased hippocampal epigenetic age in the Ts65Dn mouse model of Down Syndrome
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Self-citationDYRK1A Up-Regulation Specifically Impairs a Presynaptic Form of Long-Term Potentiation
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Mitigating Cognitive Deficits in Down Syndrome by Managing Microglia Activation
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In vivo and in vitro models for research on Down syndrome
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Adult choline supplementation in a Down syndrome model reduces co-morbidities and improves cognitionPreprint
Tallino, S., Etebari, R., McDonough, I., Leon, H., Sepulveda, I., Winslow, W., Bartholomew, S. K., Perez, S. E., Mufson, E. J., & Velázquez, R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.26.615088
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Brain metabolic and behavioral alterations in a Down syndrome model
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Amyloid precursor protein mediates deficits in corticogenesis in Down syndrome cortical organoidsPreprint
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- Authors
- Shaw, P. R., Klein, J. A., Aziz, N. M., & Haydar, T. F.
- Affiliations
- Boston University (US)
- Corresponding author
- Haydar, Tarik F.
- Venue
- Disease Models & Mechanisms
- Publisher
- The Company of Biologists
- Published
- 2020-09-01
- Volume
- 13
- Issue
- 9
- ISSN
- 1754-8403 (ISSN-L)
- 1754-8411
- PMC
- PMC7522024
- OpenAlex
- W3049706505
- Cited by
- 45
- References
- 72
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 6 · 2023: 7 · 2022: 13 · 2021: 4 · 2020: 2
- FWCI
- 4.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Disease Models & Mechanisms (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (NS076503)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Ts65Dn mouse model, Down syndrome, mouse model, phenotypic drift, brain development, neuroanatomy, learning and memory, behavioral phenotypes, longitudinal cohort comparison
- MeSH terms
- Morris Water Maze Test, Animals, Behavior, Animal, Brain, Cell Count, Cerebellum, Disease Models, Animal, Down Syndrome, Embryo, Mammalian, Female, Hindlimb, Hippocampus, Longevity, Male, Mice, Transgenic, Myelin Sheath, Oligodendroglia, Organ Size, Phenotype, Reflex, Embryonic Development
About these checks
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