scholarly journals Context Fear Conditioning in Down Syndrome Mouse Models: Effects of Trisomic Gene Content, Age, Sex and Genetic Background

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1528
Author(s):  
Md. Mahiuddin Ahmed ◽  
Aaron Block ◽  
Nicolas Busquet ◽  
Katheleen J. Gardiner
Keyword(s):  
Down Syndrome ◽  
Fear Conditioning ◽  
Mouse Models ◽  
Genetic Background ◽  
Chromosome 21 ◽  
F1 Hybrids ◽  
Male Mice ◽  
Human Chromosome 21 ◽  
The Common ◽  
Context Fear Conditioning

Down syndrome (DS), trisomy of the long arm of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability (ID). Currently, there are no effective pharmacotherapies. The success of clinical trials to improve cognition depends in part on the design of preclinical evaluations in mouse models. To broaden understanding of the common limitations of experiments in learning and memory, we report performance in context fear conditioning (CFC) in three mouse models of DS, the Dp(16)1Yey, Dp(17)1Yey and Dp(10)1Yey (abbreviated Dp16, Dp17 and Dp10), separately trisomic for the human Hsa21 orthologs mapping to mouse chromosomes 16, 17 and 10, respectively. We examined female and male mice of the three lines on the standard C57BL/6J background at 3 months of age and Dp17 and Dp10 at 18 months of age. We also examined female and male mice of Dp17 and Dp10 at 3 months of age as F1 hybrids obtained from a cross with the DBA/2J background. Results indicate that genotype, sex, age and genetic background affect CFC performance. These data support the need to use both female and male mice, trisomy of sets of all Hsa21 orthologs, and additional ages and genetic backgrounds to improve the reliability of preclinical evaluations of drugs for ID in DS.

scholarly journals The Use of Mouse Models for Understanding the Biology of Down Syndrome and Aging

2012 ◽  
Vol 2012 ◽  
pp. 1-20 ◽  
Author(s):  
Guido N. Vacano ◽  
Nathan Duval ◽  
David Patterson
Keyword(s):  
Down Syndrome ◽  
Human Chromosome ◽  
Mouse Models ◽  
Targeted Mutagenesis ◽  
Chromosome 21 ◽  
Practical Reasons ◽  
Future Directions ◽  
Human Chromosome 21 ◽  
Biology Of Aging ◽  
Chromosome Regions

Down syndrome is a complex condition caused by trisomy of human chromosome 21. The biology of aging may be different in individuals with Down syndrome; this is not well understood in any organism. Because of its complexity, many aspects of Down syndrome must be studied either in humans or in animal models. Studies in humans are essential but are limited for ethical and practical reasons. Fortunately, genetically altered mice can serve as extremely useful models of Down syndrome, and progress in their production and analysis has been remarkable. Here, we describe various mouse models that have been used to study Down syndrome. We focus on segmental trisomies of mouse chromosome regions syntenic to human chromosome 21, mice in which individual genes have been introduced, or mice in which genes have been silenced by targeted mutagenesis. We selected a limited number of genes for which considerable evidence links them to aspects of Down syndrome, and about which much is known regarding their function. We focused on genes important for brain and cognitive function, and for the altered cancer spectrum seen in individuals with Down syndrome. We conclude with observations on the usefulness of mouse models and speculation on future directions.

Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions

Gene ◽  
2003 ◽  
Vol 318 ◽  
pp. 137-147 ◽  
Author(s):  
Katheleen Gardiner ◽  
Andrew Fortna ◽  
Lawrence Bechtel ◽  
Muriel T Davisson
Keyword(s):  
Down Syndrome ◽  
Human Chromosome ◽  
Mouse Models ◽  
Chromosome 21 ◽  
Gene Content ◽  
Human Chromosome 21 ◽  
Genomic Regions ◽  
Mouse Genomic

scholarly journals Altered Hippocampal-Prefrontal Neural Dynamics in Mouse Models of Down Syndrome

2019 ◽  
Author(s):  
Pishan Chang ◽  
Daniel Bush ◽  
Stephanie Schorge ◽  
Mark Good ◽  
Tara Canonica ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Models ◽  
Cognitive Deficits ◽  
Memory Task ◽  
Chromosome 21 ◽  
Neural Dynamics ◽  
Human Chromosome 21 ◽  
Chromosomal Disorder ◽  
Reduced Frequency ◽  
High Gamma

SummaryAltered neural dynamics in medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder, Down Syndrome (DS). Here, we demonstrate non-overlapping behavioural differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice showed slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, increased modulation of hippocampal high gamma); Dp10Yey mice showed impaired alternation performance and reduced theta modulation of hippocampal low gamma; while Dp17Yey mice were no different from wildtype mice. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.

scholarly journals A non-mosaic humanized mouse model of Down syndrome, trisomy of a nearly complete long arm of human chromosome 21 in mouse chromosome background

2019 ◽  
Author(s):  
Yasuhiro Kazuki ◽  
Feng J. Gao ◽  
Yicong Li ◽  
Anna J. Moyer ◽  
Benjamin Devenney ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Human Chromosome ◽  
Mouse Models ◽  
Artificial Chromosome ◽  
Human Condition ◽  
Chromosome 21 ◽  
Humanized Mouse ◽  
Human Chromosome 21 ◽  
Functional Features

AbstractDown syndrome (DS) is a complex human condition, and animal models trisomic for human chromosome 21 (HSA21) genes or orthologs provide insights into better understanding and treating DS. However, HSA21 orthologs are distributed into three mouse chromosomes, preventing us from generating mouse models trisomy of a complete set of HSA21 orthologs. The only existing humanized mouse DS model, Tc1, carries a HSA21 with over 20% of protein coding genes (PCGs) disrupted. More importantly, due to the human centromere, Tc1 is mosaic (a mix of euploid and trisomic cells), which makes every mouse unique and compromises interpretation of results. Here, we used mouse artificial chromosome (MAC) technology to “clone” the 34 MB long arm of HSA21 (HSA21q). Through multiple steps of microcell-mediated chromosome transfer we created a new humanized DS mouse model, Tc(HSA21q;MAC)1Yakaz (“TcMAC21”). Constitutive EGFP expression from the transchromosome and fluorescent in situ hybridization validate that TcMAC21, containing a hybrid chromosome of HSA21q and mouse centromere, is not mosaic. Whole genome sequencing shows that TcMAC21 contains a nearly complete copy of HSA21q with 93% of intact PCGs, while RNA-seq and additional mRNA/protein expression analyses confirm that PCGs are transcribed and regulated. A battery of tests show that TcMAC21 recapitulates many DS phenotypes including morphological anomalies in heart, craniofacial skeleton and brain, pathologies at molecular and cellular level, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research.Significance StatementIn the last 25 years, mouse models of trisomy 21 have supported research into Down syndrome, from defining the basis for developmental effects up to support for clinical trials. However, existing models have significant shortfalls, especially for preclinical studies. These deficiencies include incomplete or inappropriate representation of trisomic genes, absence of an extra chromosome, and mosaicism.Using cutting edge technologies we produced a mouse artificial chromosome containing the entire 34Mb long arm of human chromosome 21 and, with assisted reproductive technologies, established it in the germ line of mice. This trisomic mouse manifests developmental and functional features of Down syndrome, including hippocampal-based learning and memory deficits. This is the most complete model of Down syndrome produced to date.

scholarly journals The first transchromosomic rat model with human chromosome 21 shows robust Down syndrome features

2021 ◽  
Author(s):  
Yasuhiro Kazuki ◽  
Feng J Gao ◽  
Miho Yamakawa ◽  
Masumi Hirabayashi ◽  
Kanako Kazuki ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Human Chromosome ◽  
Mouse Models ◽  
Rat Model ◽  
Heart Development ◽  
Basic Research ◽  
Craniofacial Morphology ◽  
Chromosome 21 ◽  
Brain Morphology ◽  
Human Chromosome 21

Progress in earlier detection and symptom management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available due to technical challenges. We developed the first transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein coding genes. RNA-Seq of neonatal forebrains demonstrates that TcHSA21rat not only expresses HSA21 genes but also has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, a prominent feature of DS that is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.

Of mice and Down syndrome

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 472-472 ◽  
Author(s):  
Jeffrey W. Taub
Keyword(s):  
Down Syndrome ◽  
Human Chromosome ◽  
Chromosome 21 ◽  
Ts65dn Mouse ◽  
Human Chromosome 21 ◽  
Shed Light

Analyzing hematopoiesis in the Ts65Dn mouse, which is trisomic for many orthologs of human chromosome 21 genes, may shed light on leukemogenesis in Down syndrome, as demonstrated by Kirsammer and colleagues in this issue.

scholarly journals Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR‐DSCR) on human chromosome 21

2019 ◽  
Vol 7 (8) ◽  
Author(s):  
Maria Chiara Pelleri ◽  
Elena Cicchini ◽  
Michael B. Petersen ◽  
Lisbeth Tranebjærg ◽  
Teresa Mattina ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Human Chromosome ◽  
Critical Region ◽  
Trisomy 21 ◽  
Partial Trisomy ◽  
Chromosome 21 ◽  
Human Chromosome 21

Complex chromosomal rearrangements of human chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome

2020 ◽  
Vol 139 (12) ◽  
pp. 1555-1563 ◽  
Author(s):  
Taichi Imaizumi ◽  
Keiko Yamamoto-Shimojima ◽  
Tomoe Yanagishita ◽  
Yumiko Ondo ◽  
Eriko Nishi ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Human Chromosome ◽  
Clinical Features ◽  
Chromosomal Rearrangements ◽  
Chromosome 21 ◽  
Human Chromosome 21 ◽  
Complex Chromosomal Rearrangements
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