Investigating Brain Alterations in the Dp1Tyb Mouse Model of Down Syndrome

Navacerrada, M. E. S.; Kim, E.; Siow, B.; Ma, D.; Gonzalez, L. R.; Simmons, C.; Hayward, D.; Gibbins, D.; Singh, N.; Strydom, A.; Fisher, E. M. C.; Tybulewicz, V. L. J.; Cash, D.

doi:10.1101/2023.07.26.550698

bioRxiv · 10.1101/2023.07.26.550698

Investigating Brain Alterations in the Dp1Tyb Mouse Model of Down Syndrome

Navacerrada, M. E. S.·Kim, E.·Siow, B.·Ma, D.·Gonzalez, L. R.·Simmons, C.·Hayward, D.·Gibbins, D.·Singh, N.·Strydom, A.·Fisher, E. M. C.·Tybulewicz, V. L. J.·Cash, D.

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Abstract

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled distinct neuroanatomical and biochemical alterations in the Dp1Tyb brains. Dp1Tyb brains exhibited a smaller surface area and a rounder shape compared to WT brains. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal subregions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype.

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Navacerrada, M. E. S., Kim, E., Siow, B., Ma, D., Gonzalez, L. R., Simmons, C., Hayward, D., Gibbins, D., Singh, N., Strydom, A., Fisher, E. M. C., Tybulewicz, V. L. J., Cash, D.. 2023-07-28. Investigating Brain Alterations in the Dp1Tyb Mouse Model of Down Syndrome. https://doi.org/10.1101/2023.07.26.550698

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