Discovery and genetic localization of down syndrome cerebellar phenotypes using the Ts65Dn mouse
Abstract
Down syndrome (DS) is the most common genetic cause of mental retardation and affects many aspects of brain development. DS individuals exhibit an overall reduction in brain size with a disproportionately greater reduction in cerebellar volume. The Ts65Dn mouse is segmentally trisomic for the distal 12-15 Mb of mouse chromosome 16, a region that shows perfect conserved linkage with human chromosome 21, and therefore provides a genetic model for DS. In this study, high resolution magnetic resonance imaging and histological analysis demonstrate precise neuro- anatomical parallels between the DS and the Ts65Dn cerebellum. Cerebellar volume is significantly reduced in Ts65Dn mice due to reduction of both the internal granule layer and the molecular layer of the cerebellum. Granule cell number is further reduced by a decrease in cell density in the internal granule layer. Despite these changes in Ts65Dn cerebellar structure, motor deficits have not been detected in several tests. Reduction in granule cell density in Ts65Dn mice correctly predicts an analogous pathology in humans; a significant reduction in granule cell density in the DS cerebellum is reported here for the first time. The candidate region of genes on chromosome 21 affecting cerebellar development in DS is therefore delimited to the subset of genes whose orthologs are at dosage imbalance in Ts65Dn mice, providing the first localization of genes affecting a neuroanatomical phenotype in DS. The application of this mod…
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Ts65Dn mice exhibit deficient neurological structural phenotypes in brain regions where the current study found DYRK1A overexpression, including during perinatal or early postnatal ages.
“Ts65Dn mice do exhibit deficient neurological structural phenotypes in brain regions where we found DYRK1A overexpression including during perinatal or early postnatal ages (Baxter et al., 2000; Belichenko et al., 2004; Bianchi et al., 2010; Chakrabarti et al., 2007; Roper et al., 2006b; Stagni et al., 2016).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Baxter et al., 2000
Similar to human studies, neuronal hypocellularity has been detected in multiple structures including the cortex, cerebellum, and hippocampus in postnatal trisomic Ts65Dn animals.
“Similar to human studies, neuronal hypocellularity has been detected in multiple structures including the cortex, cerebellum, and hippocampus in postnatal trisomic animals (Insausti et al., 1998; Baxter et al., 2000; Olson et al., 2004; Roper et al., 2006; Chakrabarti et al., 2010; Aziz et al., 2018).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Baxter et al., 2000
Unlike humans, this hypocellularity does not appear to be driving persistent volumetric changes in these structures, as size deficits detected prenatally do not persist postnatally except in the cerebellum.
“However, unlike humans, this hypocellularity does not appear to be driving persistent volumetric changes in these structures, as size deficits detected prenatally (Chakrabarti et al., 2007) do not persist postnatally except in the cerebellum (Baxter et al., 2000; Olson et al., 2004).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Baxter et al., 2000
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“, 2007) do not persist postnatally except in the cerebellum (Baxter et al., 2000; Olson et al., 2004).”
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- Authors
- Baxter, L. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Baxter, L. L.
- ORCID
- Baxter, L. L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-01-22
- Volume
- 9
- Issue
- 2
- Pages
- 195-202
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2149852014
- Cited by
- 275
- References
- 2
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 7 · 2022: 11 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 7 · 2015: 13 · 2014: 11 · 2013: 13 · 2012: 12
- FWCI
- 13.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute on Aging (P50AG005146, AG 05146)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-24605, P01HD024605)
- 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
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- Down syndrome, Ts65Dn mouse model, trisomy 16, chromosome 21, cerebellum, cerebellar volume, molecular layer, cerebellar development, neuroanatomical phenotypes, gene mapping, intellectual disability
- MeSH terms
- Animals, Cell Count, Cerebellum, Crosses, Genetic, Down Syndrome, Female, Genetic Markers, Granulocytes, Humans, Magnetic Resonance Imaging, Male, Mice, Inbred A, Mice, Inbred CBA, Mice, Inbred C3H, Mice, Inbred C57BL, Motor Activity, Mice
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