Cited by 118Down syndrome and intellectual disability researchGenetics and Neurodevelopmental DisordersWilliams Syndrome Research

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Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome

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Aziz, Nadine M., Guedj, Faycal, Pennings, Jeroen L. A., Olmos-Serrano, Jose Luis, Siegel, Ashley, Haydar, Tarik F., Bianchi, Diana W.·2018·Disease Models & Mechanisms

DOI 10.1242/dmm.031013PMC PMC6031353

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Abstract

Down syndrome (DS) results from triplication of human chromosome 21. Neuropathological hallmarks of DS include atypical central nervous system development that manifests prenatally and extends throughout life. As a result, individuals with DS exhibit cognitive and motor deficits and have delays in achieving developmental milestones. To determine whether different mouse models of DS recapitulate the human prenatal and postnatal phenotypes, here we directly compared brain histogenesis, gene expression, and behavior over the lifespan of three cytogenetically distinct mouse models of DS: Ts1Cje, Ts65Dn and Dp(16)1/Yey. Histological data indicated that Ts65Dn mice were the most consistently affected with respect to somatic growth, neurogenesis, and brain morphogenesis. Embryonic and adult gene expression results showed that Ts1Cje and Ts65Dn brains had considerably more differentially expressed (DEX) genes compared to Dp(16)1/Yey mice, despite the larger number of triplicated genes in the latter model. In addition, DEX genes showed little overlap in identity and chromosomal distribution in the three models, leading to dissimilarities in affected functional pathways. Perinatal and adult behavioral testing also highlighted differences among the models in their abilities to achieve various developmental milestones and perform hippocampal- and motor-based tasks. Interestingly, Dp(16)1/Yey mice showed no abnormalities in prenatal brain phenotypes, yet they manifested behavioral deficits starting at postnatal day 15 that continued through adulthood. In contrast, Ts1Cje mice showed mildly abnormal embryonic brain phenotypes, but only select behavioral deficits as neonates and adults. Altogether, our data showed widespread and unexpected fundamental differences in behavioral, gene expression, and brain development phenotypes between these three mouse models. Our findings illustrate unique limitations of each model when studying aspects of brain development and function in DS. This work helps to inform model selection in future studies investigating how observed neurodevelopmental abnormalities arise, how they contribute to cognitive impairment, and when testing therapeutic molecules to ameliorate the intellectual disability associated with DS.

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Fig. 1. Number of DEX genes in Ts1Cje, Ts65Dn and Dp(16)1/Yey embryonic forebrains. Analysis of differentially expressed (DEX) genes in E15.5 forebrains of Ts1Cje mice (n=5 trisomic mice, n=5 euploid littermates); Ts65Dn mice (n=5 trisomic mice, n=6 euploid littermates); and Dp(16)1/Yey mice (n=6 trisomic mice, n=6 euploid littermates). A Benjamini-Hochberg FDR cut-off <10% was used to determine which genes are classified as DEX. (A) Overall number of DEX genes in each model. Ts1Cje and Ts65Dn mice display approximately double the number of DEX genes as Dp(16)1/Yey mice. (B) Number of DEX genes by chromosome in each model. (C) Venn diagram showing the number of common DEX genes among the models. (D) Distribution of dysregulated genes by fold change (FC), showing that the majority of dysregulated genes have small magnitude FCs that lie between 0.75 and 1.25. Relative gene expression in trisomic animals compared with their euploid littermates was deemed significant at P<0.05. (D′) Distribution of dysregulated genes that are common to all three models. The majority of dysregulated genes in common cluster between 0.75 and 1.25 FC.CC BY · PubMed Central

Fig. 2. Embryonic somatic growth, brain development, and neurogenesis in Ts1Cje, Ts65Dn and Dp(16)1/Yey mice. All images and data are generated at the level of the future somatosensory cortex. Data are mean±s.e.m., *P<0.05, **P<0.01. (A) Representative images of euploid and Ts65Dn embryos at E15.5. (B) Quantification of body length in Ts1Cje, Ts65Dn and Dp(16)1/Yey embryos, showing only a decrease in Ts65Dn body length. Mice used: (1) Ts1Cje strain (n=13 trisomic mice, n=11 euploid littermates); (2) Ts65Dn strain (n=7 trisomic mice, n=20 euploid littermates); (3) Dp(16)1/Yey strain (n=26 trisomic mice, n=19 euploid littermates). (C) Representative images displaying the rostrocaudal (top) and mediolateral (bottom) measurements used to assess gross brain size at E15.5. (D) Gross brain measurements in Ts1Cje, Ts65Dn and Dp(16)1/Yey mice, showing that only Ts65Dn embryonic forebrains have a decreased rostrocaudal length. Mice used: (1) Ts1Cje strain (n=13 trisomic mice, n=11 euploid littermates); (2) Ts65Dn strain (n=7 trisomic mice, n=20 euploid littermates); (3) Dp(16)1/Yey strain (n=26 trisomic mice, n=19 euploid littermates). (E) Representative image showing the dorsal pallium in E15.5 brain. Dashed lines demarcate the different layers of the germinal zone: ventricular/subventricular zones (VZ/SVZ), intermediate zone (IZ) and subplate/cortical plate (SP/CP). (F) Measures of neocortical expansion in Ts1Cje, Ts65Dn and Dp(16)1/Yey forebrains as a percentage of those of their respective euploid littermates. Ts65Dn embryos show a decrease in overall pallial thickness, as well as thickness of the IZ and SP/CP (#P=0.10). Ts1Cje embryos show an increase in the size of the IZ that is not reflected in any other layer or in overall thickness. Dp(16)1/Yey embryos show no change. Mice used: (1) Ts1Cje strain (n=6 trisomic mice, n=6 euploid littermates); (2) Ts65Dn strain (n=9 trisomic mice, n=9 euploid littermates); (3) Dp(16)1/Yey strain (n=11 trisomic mice, n=10 euploid littermates). (G) Representative image showing EdU staining (green) in the dorsal pallium. Again, the layers of the dorsal germinal zone are demarcated. (H) Ts1Cje embryos show no change in the percentage of EdU+ cells by layer in the dorsal pallium compared with euploid littermates. (I) Ts65Dn embryos show a decrease in the percentage of EdU+ cells only in the VZ/SVZ of the dorsal pallium compared with euploid littermates. (J) Dp(16)1/Yey embryos show no change in the percentage of EdU+ cells by layer in the dorsal pallium compared with euploid littermates. (K) Representative image showing OLIG2 (red) staining in the medial ganglionic eminence (MGE) of the ventral germinal zone at E15.5. Cell nuclei are stained with DAPI (blue). Mice used in H-K: (1) Ts1Cje strain (n=6 trisomic mice, n=6 euploid littermates); (2) Ts65Dn strain (n=9 trisomic mice, n=9 euploid littermates); (3) Dp(16)1/Yey strain (n=11 trisomic mice, n=10 euploid littermates). (L) Number of OLIG2+ cells per 100 µm3 of MGE in Ts1Cje, Ts65Dn and Dp(16)1/Yey embryos and their respective euploid littermates. Only Ts65Dn mice show a marked increase in OLIG2+ cells compared with euploid littermates. Mice used: (1) Ts1Cje strain (n=6 trisomic mice, n=6 euploid littermates); (2) Ts65Dn strain (n=9 trisomic mice, n=9 euploid littermates); (3) Dp(16)1/Yey strain (n=11 trisomic mice, n=10 euploid littermates). (M) Representative image showing phosphorylated histone 3 (pH3) (green) staining in the MGE of the ventral germinal zone at E15.5. Cell nuclei are stained with DAPI (blue). (N) Number of pH3+ cells in the MGE of Ts1Cje, Ts65Dn and Dp(16)1/Yey embryos and their respective euploid littermates. Only Ts65Dn mice show a significant increase in pH3+ cells compared with euploid littermates. (O-Q) Distribution of pH3+ into 20-µm bins starting at the ventricular surface. (O) Ts1Cje mice show a decrease only in one bin at 160 µm from the ventricular surface compared with euploid littermates. (P) Ts65Dn show a consistent increase in the area corresponding to the SVZ of the MGE (bins 140-260 µm from the ventricular surface) compared with euploid littermates. (Q) Dp(16)1/Yey shows no change in pH3+ cells by bin compared with euploid littermates. Mice used in N-Q: (1) Ts1Cje strain (n=6 trisomic mice, n=6 euploid littermates); (2) Ts65Dn strain (n=9 trisomic mice, n=9 euploid littermates); (3) Dp(16)1/Yey strain (n=11 trisomic mice, n=10 euploid littermates).CC BY · PubMed Central

Fig. 3. Developmental milestones in male Ts1Cje, Ts65Dn and Dp(16)1/Yey neonates. Developmental milestones were measured on a daily basis between birth and P21 in Ts1Cje mice (n=32 trisomic mice, n=64 euploid littermates); Ts65Dn mice (n=34 trisomic mice, n=23 euploid littermates); and Dp(16)1/Yey mice (n=30 trisomic mice, n=72 euploid littermates). Graphs showing day on which criteria were met on each task in trisomic mice compared with euploid littermates. Plots show median value for each group tested, first and third quartiles, data range and outliers; *P<0.05. (A) On surface righting, only Ts1Cje and Ts65Dn mice show an impairment compared with their euploid littermates. (B) On negative geotaxis, only Ts65Dn mice show a marked impairment compared with their euploid littermates. (C) On forelimb grasp, all trisomic mice perform similarly to their euploid littermates. (D) On cliff aversion, Ts1Cje and Ts65Dn mice show a significant impairment, whereas Dp(16)1/Yey mice show an improvement, compared with their respective euploid littermates. (E) On open field, all trisomic mice perform similarly to their euploid littermates. (F) On eye opening, all trisomic mice perform similarly to their euploid littermates, showing that there was no confound during testing from lack of vision in trisomic mice. (G) On air righting, all trisomic mice show an impairment compared with their euploid littermates. (H) On auditory startle, all trisomic mice show an impairment compared with their euploid littermates. (I) On ear twitch, only Dp(16)1/Yey mice show an impairment compared with euploid littermates.CC BY · PubMed Central

Fig. 4. Neuronal populations in P15 Ts1Cje, Ts65Dn and Dp(16)1/Yey forebrains. Both excitatory and inhibitory neuronal populations were measured in the somatosensory cortices of the Ts1Cje (n=6 trisomic mice, n=6 euploid littermates), Ts65Dn (n=4 trisomic mice, n=4 euploid littermates) and Dp(16)1/Yey (n=4 trisomic mice, n=5 euploid littermates) mouse models at P15. (A) Representative images of parvalbumin (PV, red), calretinin (CR, green) and somatostatin (SS, green) inhibitory interneuron (IN) staining in the somatosensory cortex. All nuclei are counterstained with DAPI (blue). (B) Cell density by neocortical layer in P15 Ts1Cje mice compared with euploids. No change is observed in density or layer thickness (data not shown). Data are mean±s.e.m. (C-E) IN density as a percentage of total cells. Each subtype is represented separately. No change in overall density or density by neocortical layer (data not shown) is seen in Ts1Cje mice compared with their euploid littermates (C). An increase in PV+ and SS+ IN density is seen in the neocortex of Ts65Dn mice compared with their euploid littermates. No change is observed in CR+ INs (D). A decrease in PV+ and SS+ IN density is seen in the neocortex of Dp(16)1/Yey mice compared with their euploid littermates. No change is observed in CR+ INs (E). (F) Representative images of PV+ (red) and SS+ (green) INs in the dorsal hippocampus. All nuclei are counterstained with DAPI (blue). (G) No change in IN populations in the hippocampus is seen in Ts1Cje (orange bars) and Dp(16)1/Yey (blue bars) mice compared with their euploid littermates. Ts65Dn mice show an increase in both PV+ and SS+ INs in the hippocampus compared with their euploid littermates. Data are mean±s.e.m., *P<0.05. (H) Representative images of Tbr1 (red) excitatory neuron staining in the somatosensory cortex. All nuclei are counterstained with DAPI (blue). (I) Ts65Dn mice show a significant decrease in excitatory neuron numbers in the somatosensory cortex compared with their euploid littermates (green bar). Dp(16)1/Yey mice show a trend towards a decrease in excitatory neuron numbers in the somatosensory cortex compared with their euploid littermates (blue bar). Ts1Cje mice show no change in overall number of excitatory neurons in the somatosensory cortex compared with their euploid littermates. (J) However, a shift in distribution from Layer IV, favoring Layer VI, is observed in these mice. Data are mean±s.e.m., *P<0.05; #P=0.07.CC BY · PubMed Central

Fig. 5. Motor-based tasks in adult Ts1Cje, Ts65Dn and Dp(16)1/Yey males. Exploratory motor behavior and coordination were investigated in the open field and rotarod tests in Ts1Cje mice (n=13 trisomic mice, n=15 euploid mice); Ts65Dn mice (n=12 trisomic mice, euploid mice=12); Dp(16)1/Yey mice(n=18 trisomic mice, n=17 euploid mice). (A-C) Measurement of distance traveled in the center versus periphery of testing space during the open field task. This measurement is a representation of exploratory behavior in animals. Ts1Cje mice travel more distance in the periphery compared with their euploid controls. Travel in the center is similar between genotypes (A). Ts65Dn mice also travel more distance in the periphery compared with their euploid controls. Travel in the center is similar between genotypes (B). Dp(16)1/Yey mice show no change in distance traveled in both center and periphery compared with their euploid controls (C). (D-F) Latency to fall during the nonaccelerating rotarod at three different speeds: 16, 24 and 32 RPM. This task measures motor coordination in animals. Ts1Cje mice only show a deficit at the highest rotational speed of 32 RPM (D). Ts65Dn mice show no difference in rotarod performance compared with a pooled cohort of B6C3Sn hybrid euploids at any speed (E). Dp(16)1/Yey mice show a marked impairment in rotarod performance at every speed compared with their euploid controls (F). (G-I) Latency to fall during the accelerating rotarod task, which gradually increases in rotational speed from 4 RPM to 40 RPM. This task measures motor coordination in animals. Ts1Cje mice show significant impairment in accelerating rotarod task compared with their euploid controls (G). Ts65Dn mice show no difference in rotarod performance compared with a pooled cohort of B6C3Sn hybrid euploids (H). Dp(16)1/Yey mice show a marked impairment in rotarod performance compared with their euploid controls (I). Data are mean±s.d., *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.CC BY · PubMed Central

Fig. 6. Hippocampal-based tasks in adult Ts1Cje, Ts65Dn and Dp(16)1/Yey males. Hippocampal-dependent spatial and contextual memory were investigated using the fear conditioning and Morris water maze (MWM) tests. (A-F) The contextual fear conditioning test has two phases: training and testing. During the training phase, mice are given two mild shocks 60 s apart. On the following day, mice are placed in the same chamber but no shocks are applied. Freezing behavior is documented. Animals used in A-F: Ts1Cje mice (n=13 trisomic mice, n=15 euploid mice); Ts65Dn (n=12 trisomic mice, n=12 euploid mice); and Dp(16)1/Yey mice (n=18 trisomic mice, n=17 euploid littermates). (G-I) The MWM test has two phases: acquisition and reversal. Both tests utilize a hidden platform to analyze learning (acquisition phase) and reversal learning (reversal phase). Mice are initially tested using a visible platform to exclude any confounds related to testing procedures or non-learning based deficits in the mice. Ts1Cje males show no deficits during either the acquisition phase or the reversal learning phase (G). Ts65Dn males show no deficits during the acquisition period after the 4 days needed to stop thigmotaxic behavior and acclimate to the task (previously published in Olmos-Serrano et al., 2016b). However, these mice show a deficit in reversal learning compared with their euploid controls (H). Dp(16)1/Yey males show impaired learning on days 1 and 5 of the acquisition phase. Additionally, these males also show a strong deficit in reversal learning compared with their euploid controls (I). Animals used in G-I: Ts1Cje mice (n=13 trisomic mice, n=11 euploid mice); Ts65Dn (n=14 trisomic mice, n=14 euploid mice); and Dp(16)1/Yey mice (n=13 trisomic mice, n=11 euploid littermates). Data are mean±s.d., *P<0.05.CC BY · PubMed Central

Fig. 7. Number of DEX genes and their chromosomal clustering in adult Ts1Cje, Ts65Dn and Dp(16)1/Yey brains by region. Global gene expression analysis of cortex, hippocampus and cerebellum in adult male Ts1Cje mice (n=5 per genotype); Ts65Dn mice (n=5 per genotype); and Dp(16)1/Yey mice (n=5 per genotype). DEX genes were designated as such using a Benjamini-Hochberg FDR cut-off of <10%. (A-C) Overall number of DEX genes in each model by region. Dp(16)1/Yey mice display the lowest number of total DEX genes. Ts1Cje and Ts65Dn mice display a similar number of total DEX genes to one another, but these genes differ in identity and in chromosomal location in each model (G-I). (D-F) Venn diagrams showing the number of common DEX genes among the models by brain region. (G-I) Analysis showing genome-wide chromosomal clustering of DEX genes in Ts1Cje mice, Ts65Dn mice and Dp(16)1/Yey mice by brain region.CC BY · PubMed Central

Fig. 8. Number of dysregulated genes by FC in adult male Ts1Cje, Ts65Dn and Dp(16)1/Yey brains by region. (A-C) Distribution of dysregulated genes in each brain region by FC, showing that the majority of dysregulated genes have small magnitude FCs that lie between 0.75 and 1.25. These genes show a significant FC value in trisomic mice compared with their euploid controls, P<0.05. (A′-C′) Distribution of dysregulated genes that are common to all three models, displayed by brain region. The majority of dysregulated genes in common cluster between 0.8 and 1.3 FC.CC BY · PubMed Central

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Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome
Navarro-Romero, A., Vázquez‐Oliver, A., Gomis‐González, M., Garzón-Montesinos, C., Falcón‐Moya, R., Pastor, A., Martín‐García, E., Pizarro, N., Busquets-García, A., Revest, J., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.01.014 · Cited by 39
The Impact of Mmu17 Non-Hsa21 Orthologous Genes in the Ts65Dn Mouse Model of Down Syndrome: The Gold Standard Refuted
Guedj, F., Kane, E., Bishop, L. A., Pennings, J. L. A., Hérault, Y., & Bianchi, D. W. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.02.012 · Cited by 36
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Advances and Applications of Brain Organoids
Li, Y., Zeng, P.-M., Wu, J., & Luo, Z. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-023-01065-2 · Cited by 40
Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of down syndrome-related phenotypes.
Lana-Elola, E., Cater, H., Watson-Scales, S., Greenaway, S., Müller-Winkler, J., Gibbins, D., Nemes, M., Slender, A., Hough, T., Keskivali-Bond, P., et al. (2021) · Disease Models & Mechanisms · doi:10.1242/dmm.049157 · Cited by 35
Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal‐derived extracellular vesicles
Perluigi, M., Picca, A., Montanari, E., Calvani, R., Marini, F., Matassa, R., Tramutola, A., Villani, A., Familiari, G., Domenico, F. D., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12499 · Cited by 35
A multi-level developmental approach to exploring individual differences in Down syndrome: genes, brain, behaviour, and environment
Thomas, M. S. C., Ojinaga-Alfageme, O., D’Souza, H., Patkee, P. A., Rutherford, M., Mok, K. Y., Hardy, J., & Karmiloff‐Smith, A. (2020) · Research in Developmental Disabilities · doi:10.1016/j.ridd.2020.103638 · Cited by 32
Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model
Guedj, F., Siegel, A. E., Pennings, J. L. A., Alsebaa, F., Massingham, L. J., Tantravahi, U., & Bianchi, D. W. (2020) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2020.10.001 · Cited by 31
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JAK inhibition decreases the autoimmune burden in Down syndrome
Rachubinski, A. L., Wallace, E., Gurnee, E., Enriquez-Estrada, B. A., Worek, K. R., Smith, K. P., Araya, P., Waugh, K. A., Granrath, R. E., Britton, E., et al. (2024) · eLife · doi:10.7554/elife.99323 · Cited by 32
Dysregulated systemic metabolism in a Down syndrome mouse model
Sarver, D. C., Xu, C., Vélez, L. M., Aja, S. M., Jaffe, A. E., Seldin, M. M., Reeves, R. H., & Wong, G. W. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101666 · Cited by 32
Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior
Edlow, A. G., Guedj, F., Sverdlov, D., Pennings, J. L. A., & Bianchi, D. W. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01335 · Cited by 30
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The innate immune system stimulating cytokine GM-CSF improves learning/memory and interneuron and astrocyte brain pathology in Dp16 Down syndrome mice and improves learning/memory in wild-type mice
Ahmed, M. M., Wang, A. C., Elos, M. T., Chial, H. J., Sillau, S., Solano, D. A., Coughlan, C. M., Aghili, L., Anton, P. E., Markham, N. E., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105694 · Cited by 31
Brain circuit pathology in Down syndrome: from neurons to neural networks
Bartesaghi, R. (2023) · Reviews in the Neurosciences · doi:10.1515/revneuro-2022-0067 · Cited by 25
Intranasal Administration of KYCCSRK Peptide Rescues Brain Insulin Signaling Activation and Reduces Alzheimer’s Disease-like Neuropathology in a Mouse Model for Down Syndrome
Tramutola, A., Lanzillotta, S., Aceto, G., Pagnotta, S. E., Ruffolo, G., Cifelli, P., Marini, F., Ripoli, C., Palma, E., Grassi, C., et al. (2023) · Antioxidants · doi:10.3390/antiox12010111 · Cited by 27
Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome
Lee, S. E., Duran-Martinez, M., Khantsis, S., Bianchi, D. W., & Guedj, F. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.10.001 · Cited by 25
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Dissection of a down syndrome-associated trisomy to separate the gene dosage-dependent and -independent effects of an extra chromosome
Xing, Z., Li, Y., Cortes-Gomez, E., Jiang, X., Gao, S., Pao, A., Shan, J., Song, Y., Perez, A., Yu, T., et al. (2023) · Human Molecular Genetics · doi:10.1093/hmg/ddad056 · Cited by 23
Attitudes Toward Hypothetical Uses of Gene-Editing Technologies in Parents of People with Autosomal Aneuploidies
Beckman, E. S., Deuitch, N. T., Michie, M., Allyse, M. A., Riggan, K. A., & Ormond, K. E. (2019) · The CRISPR Journal · doi:10.1089/crispr.2019.0021 · Cited by 25
Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
Fulton, S. L., Wenderski, W., Lepack, A. E., Eagle, A. L., Fanutza, T., Bastle, R. M., Ramakrishnan, A., Hays, E. C., Neal, A., Bendl, J. M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34200-0 · Cited by 20
Type I interferon signalling and interferon‐responsive microglia in health and disease
López‐Atalaya, J. P., & Bhojwani-Cabrera, A. M. (2025) · FEBS Journal · doi:10.1111/febs.70126 · Cited by 23
Subtle Roles of Down Syndrome Cell Adhesion Molecules in Embryonic Forebrain Development and Neuronal Migration
Mitsogiannis, M. D., Pancho, A., Aerts, T., Sachse, S., Vanlaer, R., Noterdaeme, L., Schmucker, D., & Seuntjens, E. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.624181 · Cited by 22
Placental development and function in trisomy 21 and mouse models of Down syndrome: Clues for studying mechanisms underlying atypical development
Adams, A. D., Guedj, F., & Bianchi, D. W. (2019) · Placenta · doi:10.1016/j.placenta.2019.10.002 · Cited by 18
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Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome
Moyer, A. J., Fernandez, F., Li, Y., Klinedinst, D. K., Florea, L., Kazuki, Y., Oshimura, M., & Reeves, R. H. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.049712 · Cited by 18
Down syndrome: A curative prospect?
Rondal, J. A. (2020) · AIMS neuroscience · doi:10.3934/neuroscience.2020012 · Cited by 14
Behavioral Phenotyping for Down Syndrome in Mice
Roper, R. J., Goodlett, C. R., de Lagrán, M. M., & Dierssen, M. (2020) · Current Protocols in Mouse Biology · doi:10.1002/cpmo.79 · Cited by 14
Deficits in Seizure Threshold and Other Behaviors in Adult Mice without Gross Neuroanatomic Injury after Late Gestation Transient Prenatal Hypoxia
Cristancho, A. G., Gadra, E. C., Samba, I., Zhao, C., Ouyang, M., Magnitsky, S. G., Huang, H., Viaene, A. N., Anderson, S. A., & Marsh, E. D. (2022) · Developmental Neuroscience · doi:10.1159/000524045 · Cited by 14
Biphasic cell cycle defect causes impaired neurogenesis in down syndrome
Sharma, V., Nehra, S., Do, L. H., Ghosh, A., Deshpande, A. J., & Singhal, N. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1007519 · Cited by 14
National Institute on Drug Abuse genomics consortium white paper: Coordinating efforts between human and animal addiction studies
Cates, H. M., Benca‐Bachman, C. E., de Guglielmo, G., Schoenrock, S. A., Shu, C., & Kallupi, M. (2019) · Genes Brain & Behavior · doi:10.1111/gbb.12577 · Cited by 14
From neurodevelopment to neurodegeneration: utilizing human stem cell models to gain insight into Down syndrome
Watson, L. A., & Meharena, H. S. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1198129 · Cited by 13
Interferon receptor gene dosage determines diverse hallmarks of Down syndromePreprint
Waugh, K. A., Minter, R., Baxter, J. A., Chi, C., Tuttle, K. D., Eduthan, N. P., Galbraith, M. D., Kinning, K. T., Andrysík, Z., Araya, P., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.03.478982 · Cited by 14
Neocortical neuronal production and maturation defects in the TcMAC21 mouse model of Down syndrome
Kurabayashi, N., Fujii, K., Otobe, Y., Hiroki, S., Hiratsuka, M., Yoshitane, H., Kazuki, Y., & Takao, K. (2023) · iScience · doi:10.1016/j.isci.2023.108379 · Cited by 13
Altered mitochondrial unfolded protein response and protein quality control promote oxidative distress in down syndrome brain
Lanzillotta, S., Esteve, D., Lanzillotta, C., Tramutola, A., Lloret, A., Forte, E., Pesce, V., Picca, A., Domenico, F. D., Marzia Perluigi, A., et al. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.11.043 · Cited by 14
Early impacts of modified food consistency on oromotor outcomes in mouse models of Down syndrome
Glass, T. J., Twadell, S., Valmadrid, L. C., & Connor, N. P. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2018.11.031 · Cited by 12
Chr21 protein–protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer’s disease
Viard, J., Loe-Mie, Y., Daudin, R., Khelfaoui, M., Plançon, C., Boland, A., Tejedor, F. J., Huganir, R. L., Kim, E., Kinoshita, M., et al. (2022) · Life Science Alliance · doi:10.26508/lsa.202101205 · Cited by 12
Building the Future Therapies for Down Syndrome: The Third International Conference of the T21 Research Society
Dierssen, M., Hérault, Y., Helguera, P. R., de Lagrán, M. M., Vázquez, A. V., Christian, B. T., Carmona‐Iragui, M., Wiseman, F. K., Mobley, W. C., Fisher, E., et al. (2021) · Molecular Syndromology · doi:10.1159/000514437 · Cited by 11
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Sexually dimorphic DYRK1A overexpression on postnatal day 15 in the Ts65Dn mouse model of down syndrome: effects of pharmacological targeting on behavioral phenotypes
Hawley, L. E., Prochaska, F., Stringer, M., Goodlett, C. R., & Roper, R. J. (2022) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2022.173404 · Cited by 11
Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model
Hawley, L. E., Stringer, M., Deal, A. J., Folz, A., Goodlett, C. R., & Roper, R. J. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106359 · Cited by 10
Inverse Comorbidity between Down Syndrome and Solid Tumors: Insights from In Silico Analyses of Down Syndrome Critical Region Genes
Fosu, K., Quarshie, J. T., Sarpong, K. A. N., & Aikins, A. R. (2023) · Genes · doi:10.3390/genes14040800 · Cited by 10
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
Llambrich, S., González, R., Albaigès, J., Wouters, J., Marain, F., Himmelreich, U., Sharpe, J. A., Dierssen, M., Gsell, W., Martínez‐Abadías, N., et al. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.815739 · Cited by 8
Ultrasonic vocalization phenotypes in the Ts65Dn and Dp(16)1Yey mouse models of Down syndrome
Glass, T. J., Lenell, C., Fisher, E. H., Yang, Q., & Connor, N. P. (2023) · Physiology & Behavior · doi:10.1016/j.physbeh.2023.114323 · Cited by 9
Influence of allelic differences in Down syndrome
Roper, R. J., Hawley, L. E., & Goodlett, C. R. (2020) · Progress in brain research · doi:10.1016/bs.pbr.2019.09.001 · Cited by 9
Spatiotemporal development of spinal neuronal and glial populations in the Ts65Dn mouse model of down syndrome.
Aziz, N. M., Klein, J. A., Brady, M. R., Olmos-Serrano, J. L., Gallo, V., & Haydar, T. F. (2019) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-019-9294-9 · Cited by 9
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Genes Associated with Disturbed Cerebral Neurogenesis in the Embryonic Brain of Mouse Models of Down Syndrome
Ishihara, K. (2021) · Genes · doi:10.3390/genes12101598 · Cited by 8
Coat Color-Facilitated Efficient Generation and Analysis of a Mouse Model of Down Syndrome Triplicated for All Human Chromosome 21 Orthologous Regions
Li, Y., Xing, Z., Yu, T., Pao, A., Daadi, M. M., & Yu, Y. E. (2021) · Genes · doi:10.3390/genes12081215 · Cited by 10
Multisensory gamma stimulation enhances adult neurogenesis and improves cognitive function in male mice with Down Syndrome
Islam, R., Jackson, B., Naomi, M. T., Schatz, B., Tan, N., Murdock, M. H., Park, D. S., Rodrígues-Amorím, D., Jiang, X., Pineda, S. S., et al. (2025) · PLoS ONE · doi:10.1371/journal.pone.0317428 · Cited by 8
ViceCT and whiceCT for simultaneous high-resolution visualization of craniofacial, brain and ventricular anatomy from micro-computed tomography
Llambrich, S., Wouters, J., Himmelreich, U., Dierssen, M., Sharpe, J. A., Gsell, W., Martínez‐Abadías, N., & Velde, G. V. (2020) · Scientific Reports · doi:10.1038/s41598-020-75720-3 · Cited by 8
From the lab to the people: major challenges in the biological treatment of Down syndrome
Rondal, J. A. (2021) · AIMS neuroscience · doi:10.3934/neuroscience.2021015 · Cited by 8
Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model
Araya, P., Niemeyer, B., Schade, K., Dunn, L. N., Waugh, K., Busquet, N., Brindley, C., Brown, C., Winkler, C., Lyford, H. R., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113130 · Cited by 7
“We next tested motor coordination using the accelerating rotarod test DS-AD mice (Data S4), and consistent with previous reports, 38,40 we found that Dp16 mice exhibit impaired motor co-ordination at 3 and 5 months of age relative to WT littermates, with a trend toward poorer performance at 7 and 9…”
Influential
Beta cell function and global glucose metabolism are impaired in Dp(16)1Yey mouse model of Down syndrome
Tolu, S., Hamzé, R., Moreau, M., Bertrand, R., Janel, N., & Movassat, J. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16155 · Cited by 7
Embryonic statistical analyses reveal 2 growth phenotypes in mouse models of Down syndrome
Adams, A. D., Lin, J., Bianchi, D. W., Bishop, L. A., Sato, T., Baxter, L. L., Hoffmann, V. J., Koehly, L. M., & Guedj, F. (2023) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2023.07.056 · Cited by 7
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Differential expression of the neuronal CB1 cannabinoid receptor in the hippocampus of male Ts65Dn Down syndrome mouse model
Franco, N. D., Drutel, G., Roullot, V., Julio‐Kalajzić, F., Lalanne, V., Grel, A., Lesté-Lasserre, T., Matias, I., Cannich, A., Gonzales, D., et al. (2022) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2022.103705 · Cited by 9
Context Fear Conditioning in Down Syndrome Mouse Models: Effects of Trisomic Gene Content, Age, Sex and Genetic Background
Ahmed, M. M., Block, A., Busquet, N., & Gardiner, K. (2021) · Genes · doi:10.3390/genes12101528 · Cited by 8
Regional redistribution of CB1 cannabinoid receptors in human foetal brains with Down's syndrome and their functional modifications in Ts65Dn +/+ mice
Patthy, Á., Hanics, J., Zachár, G., Kovács, G. G., Harkany, T., & Alpár, A. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12887 · Cited by 6
Developmental Brain Injury and Social Determinants of Health: Opportunities to Combine Preclinical Models for Mechanistic Insights into Recovery
Guez‐Barber, D., Eisch, A. J., & Cristancho, A. G. (2023) · Developmental Neuroscience · doi:10.1159/000530745 · Cited by 8
Decrease in the T-box1 gene expression in embryonic brain and adult hippocampus of down syndrome mouse models.
Shimizu, R., Ishihara, K., Kawashita, E., Sago, H., Yamakawa, K., Mizutani, K.-I., & Akiba, S. (2020) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2020.12.026 · Cited by 3
Novel insights from fetal and placental phenotyping in 3 mouse models of Down syndrome
Adams, A. D., Hoffmann, V. J., Koehly, L. M., Guedj, F., & Bianchi, D. W. (2021) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2021.03.019 · Cited by 5
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Pro-inflammatory Cytokine GM-CSF Improves Learning/Memory and Brain Pathology in Dp16 Down Syndrome Mice and Improves Learning/Memory in Wild-Type MicePreprint
Ahmed, M. M., Wang, A. C.-J., Elos, M. T., Chial, H. J., Sillau, S. H., Solano, D., Coughlan, C. M., Aghili, L., Anton, P., Markham, N., et al. (2021) · bioRxiv · doi:10.1101/2021.07.04.451073 · Cited by 2
Altered synaptic functions in a humanized mouse model of down syndrome (TcMAC21): Implications for seizure susceptibility
Shao, L., & Stafstrom, C. E. (2025) · Epilepsy Research · doi:10.1016/j.eplepsyres.2025.107686 · Cited by 4
Early Chronic Fluoxetine Treatment of Ts65Dn Mice Rescues Synaptic Vesicular Deficits and Prevents Aberrant Proteomic Alterations
Fatemi, S. H., Otte, E. D., Folsom, T. D., Eschenlauer, A. C., Roper, R. J., Aman, J. W., & THURAS, P. D. (2024) · Genes · doi:10.3390/genes15040452 · Cited by 4
Complement pathway dysregulation and astrocyte alterations in Down syndrome: evidence from postmortem brain tissue and iPSC-derived astrocytes
Silva, A. L. T. E., de Oliveira, P. H. P., Yokota-Moreno, B. Y., Fausto, J. D. S., Avila, J. P., Nakaya, H. I., Sertie, A. L., & Zampieri, B. L. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02090-0 · Cited by 5
Dissecting the contribution of human chromosome 21 syntenic regions to recognition memory processes in adult and aged mouse models of Down syndrome
Canonica, T., Kidd, E. J., Gibbins, D., Lana‐Elola, E., Fisher, E., Tybulewicz, V. L. J., & Good, M. A. (2024) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2024.1428146 · Cited by 4
Characterization of Apathy-Like Behaviors in Mouse Models of Down Syndrome
Zhang, T., Wang, X., Jester, H. M., Zhou, X., & Ma, T. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240675 · Cited by 3
Early postnatal GABAB antagonist treatment normalizes inhibitory/excitatory balance in neonatal Ts65Dn mice, a genetic model of down syndrome
Jin, J., Doan, J., Fernandez, C., Nguyen, S., Spencer, C., & Kleschevnikov, A. M. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115171 · Cited by 3
Visual discrimination and inhibitory control deficits in mouse models of Down syndrome: A pilot study using rodent touchscreen technology
Siegel, A. E., Bianchi, D. W., & Guedj, F. (2023) · Journal of Neuroscience Research · doi:10.1002/jnr.25160 · Cited by 4
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Down syndrome is associated with altered frequency and functioning of tracheal multiciliated cells, and response to influenza virus infection
Thomas, S. N., Niemeyer, B. F., Jiménez-Valdés, R. J., Kaiser, A. J., Espinosa, J. M., Sullivan, K. D., Goodspeed, A. E., Costello, J. C., Alder, J. K., Cañas‐Arranz, R., et al. (2023) · iScience · doi:10.1016/j.isci.2023.107361 · Cited by 3
JAK inhibition decreases the autoimmune burden in Down syndromePreprint
Rachubinski, A. L., Wallace, E. B., Gurnee, E., Estrada, B. A. E., Worek, K. R., Smith, K. P., Araya, P., Waugh, K. A., Granrath, R. E., Britton, E. C., et al. (2024) · eLife · doi:10.7554/elife.99323.1 · Cited by 3
Disrupted Neurogenesis from Basal Intermediate Precursor Cells Alters the Postnatal Neocortex in the TcMAC21 Mouse Model of Down Syndrome
Atak, Z., Srivastava, A., Gandhi, S., Park, E., Williams, J., Torii, M., & Haydar, T. F. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.0040-25.2025 · Cited by 2
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Neurogenesis, Myelination, and Circuitry: The Case for a Distributed Therapeutic Regimen in Down Syndrome
Haydar, T. F. (2020) · American Journal on Intellectual and Developmental Disabilities · doi:10.1352/1944-7558-125.2.100 · Cited by 3
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Mitigating Cognitive Deficits in Down Syndrome by Managing Microglia Activation
Shaw, P. R., & Haydar, T. F. (2020) · Neuron · doi:10.1016/j.neuron.2020.11.017 · Cited by 2
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Translating the Human CANTAB Touchscreen Based Tasks to Evaluate Learning and Memory in Mouse Models of Down SyndromePreprint
Siegel, A. E., Bianchi, D. W., & Guedj, F. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.21.214106 · Cited by 2
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The impact of Mmu 17 non- Hsa 21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the “gold standard” revisitedPreprint
Guedj, F., Kane, E., Bishop, L. A., Pennings, J. L. A., Hérault, Y., & Bianchi, D. W. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.23.509067 · Cited by 2
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Complement system alteration in iPSC-derived astrocytes from individuals with Down syndromePreprint
Silva, A. L. T. E., de Oliveira, P. H. P., Yokota-Moreno, B. Y., Avila, J. P., Nakaya, H. I., Fausto, J. D. S., Sertie, A. L., & Zampieri, B. L. (2024) · Research Square · doi:10.21203/rs.3.rs-5319960/v1 · Cited by 2
A Simplified Paradigm of Late Gestation Transient Prenatal Hypoxia to Investigate Functional and Structural Outcomes from a Developmental Hypoxic Insult
Gadra, E. C., & Cristancho, A. G. (2022) · BIO-PROTOCOL · doi:10.21769/bioprotoc.4519 · Cited by 1
Foot Muscle Exercise: A Novel Approach to Improve Motor Functions in Children with Down Syndrome Having Pes Planus – A Randomized Controlled Trial
Adeeb, N., Farooqui, S. I., Hasan, Z. M., Khan, A., & Rizvi, J. (2024) · Developmental Neurorehabilitation · doi:10.1080/17518423.2024.2365798 · Cited by 1
Mapping behavioral landscapes in Down syndrome animal models
de Lagrán, M. M. (2020) · Progress in brain research · doi:10.1016/bs.pbr.2020.01.005 · Cited by 1
Modeling Down Syndrome Neurodevelopment with Dosage Compensation
Czerminski, J. T. (2019) · eScholarship@UMassChan · doi:10.13028/j7xf-1q21 · Cited by 1
Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model
Llambrich, S., Tielemans, B., Saliën, E., Atzori, M., Wouters, K., Bulck, V. V., Platt, M., Vanherp, L., Fernandez, N. G., de la Fuente, L. G., et al. (2023) · eLife · doi:10.1101/2023.07.31.551282 · Cited by 6
JAK inhibition decreases the autoimmune burden in Down syndromePreprint
Rachubinski, A. L., Wallace, E. B., Gurnee, E., Estrada, B. A. E., Worek, K. R., Smith, K. P., Araya, P., Waugh, K. A., Granrath, R. E., Britton, E. C., et al. (2024) · eLife · doi:10.7554/elife.99323.2 · Cited by 1
Cognitive function in mice with segmental trisomy of human chromosome 21 Down Syndrome genes
Canonica, T. (2019) · ORCA Online Research @Cardiff (Cardiff University)
Detection of Novel Genes on Recessive Heterozygous Alleles in Pig Breeding: A Review
Tran, H. T., Linh, N. T., Le, T. M., Nam, T. V., & Bui, A. P. N. (2022) · Indian Journal of Animal Research · doi:10.18805/ijar.bf-1486
Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse modelPreprint
Llambrich, S., Tielemans, B., Saliën, E., Atzori, M., Wouters, K., Bulck, V. V., Platt, M., Vanherp, L., Fernandez, N. G., de la Fuente, L. G., et al. (2023) · eLife · doi:10.7554/elife.89763.1
Epigenetic Correction and Early Brain Pharmacotherapy in Down Syndrome
Rondal, J. A. (2024) · International Journal of Clinical Psychiatry and Mental Health · doi:10.12970/2310-8231.2024.12.01

Authors: Aziz, N. M., Guedj, F., Pennings, J. L. A., Olmos-Serrano, J. L., Siegel, A., Haydar, T. F., & Bianchi, D. W.
Affiliations: Boston University (US)
National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
National Institute for Public Health and the Environment (NL)
National Institutes of Health (US)
Corresponding author: Aziz, Nadine M.
ORCID: Aziz, Nadine M.
Guedj, Faycal
Pennings, Jeroen L. A.
Siegel, Ashley
Haydar, Tarik F.
Bianchi, Diana W.
Venue: Disease Models & Mechanisms
Publisher: The Company of Biologists
Published: 2018-01-01
Volume: 11
Issue: 6
ISSN: 1754-8403 (ISSN-L)
1754-8411
DOI: 10.1242/dmm.031013
PMC: PMC6031353
OpenAlex: W2801858511
Cited by: 118
References: 135
Citations by year: 2026: 4 · 2025: 12 · 2024: 19 · 2023: 21 · 2022: 16 · 2021: 13 · 2020: 18 · 2019: 13 · 2018: 2
FWCI: 10.97
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/3.0 (am, 1233 d)
Locations: Disease Models & Mechanisms (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
HighWire Press Open Archive (submittedVersion)
Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
Rivm (National Institute for Public Health and the Environment) (submittedVersion)
Funders: National Institutes of Health (R01NS076503, R01HD058880)
Illumina (250-10396-12547000001)
Anna and John J. Sie Foundation (250-10488-40026002016)
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, mouse models of Down syndrome, brain development, neurogenesis, brain morphogenesis, physical growth, differentially expressed genes, gene expression, intellectual disability, motor behavior, model comparison
MeSH terms: Animals, Animals, Newborn, Behavior, Animal, Brain, Disease Models, Animal, Down Syndrome, Female, Gene Expression Regulation, Hippocampus, Longevity, Male, Mice, Inbred C57BL, Motor Activity, Neurons, Phenotype, Genome, Neurogenesis

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Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome

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