Abstract
Background
Despite successful preclinical treatment studies to improve neurocognition in the
Ts65Dn mouse model of Down syndrome, translation to humans has failed. This raises
questions about the appropriateness of the Ts65Dn mouse as the “gold standard.” We
used the novel Ts66Yah mouse that carries an extra chromosome and the identical segmental
Mmu16 trisomy as Ts65Dn without the Mmu17 non-orthologous region.
Methods
Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate
controls, were used for gene expression and pathway analyses. Behavioral experiments
were performed in neonatal and adult mice. Since male Ts66Yah mice are fertile, parent
of origin transmission of the extra chromosome was studied.
Results
Forty-five protein coding genes mapped to the Ts65Dn Mmu17 non-orthologous region; 71-82% are expressed during forebrain development. Several
of these genes are uniquely overexpressed in Ts65Dn embryonic forebrain producing
major differences in dysregulated genes and pathways. Despite these differences, the
primary Mmu16 trisomic effects were highly conserved in both models, resulting in commonly dysregulated
disomic genes and pathways. Delays in motor development, communication and olfactory
spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult
Ts66Yah mice showed milder working memory deficits and sex-specific effects in exploratory
behavior and spatial hippocampal memory, while long-term memory was preserved.
Conclusions
Our findings suggest that triplication of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain
why preclinical trials that used this model have unsuccessfully translated to human
therapies.
Key Words
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Article info
Publication history
Accepted:
February 8,
2023
Received in revised form:
February 7,
2023
Received:
September 26,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Handling Editor: Dr. J.R. Krystal
This research was supported in part by the intramural program of the National Human Genome Research Institute at the National Institutes of Health
Author Contributions:
Conceptualization: F.G., D.W.B.
Methodology: F.G., J.L.A.P., L.A.B., E.K., Y.H., D.W.B.
Validation: F.G., J.L.A.P., E.K., D.W.B.
Formal analysis: F.G., J.L.A.P.
Investigation: F.G., J.L.A.P., D.W.B.
Writing – original draft: F.G., D.W.B.
Writing - review & editing: F.G., J.L.A.P., L.A.B., E.K., Y.H., D.W.B.
Disclosures
The authors report no biomedical financial interests or potential conflicts of interest.
Data Availability
All gene expression data have been deposited into the Gene Expression Omnibus (GEO). The GSE identifier is GSE222355.
Identification
Copyright
Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
