scholarly journals From Abnormal Hippocampal Synaptic Plasticity in Down Syndrome Mouse Models to Cognitive Disability in Down Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Nathan Cramer ◽  
Zygmunt Galdzicki
Keyword(s):  
Down Syndrome ◽  
Synaptic Plasticity ◽  
Mouse Models ◽  
Cognitive Processes ◽  
Functional Change ◽  
Chromosome 21 ◽  
Cognitive Disability ◽  
Ts65dn Mouse ◽  
Hippocampal Synaptic Plasticity ◽  
Hippocampal Networks

Down syndrome (DS) is caused by the overexpression of genes on triplicated regions of human chromosome 21 (Hsa21). While the resulting physiological and behavioral phenotypes vary in their penetrance and severity, all individuals with DS have variable but significant levels of cognitive disability. At the core of cognitive processes is the phenomenon of synaptic plasticity, a functional change in the strength at points of communication between neurons. A wide variety of evidence from studies on DS individuals and mouse models of DS indicates that synaptic plasticity is adversely affected in human trisomy 21 and mouse segmental trisomy 16, respectively, an outcome that almost certainly extensively contributes to the cognitive impairments associated with DS. In this review, we will highlight some of the neurophysiological changes that we believe reduce the ability of trisomic neurons to undergo neuroplasticity-related adaptations. We will focus primarily on hippocampal networks which appear to be particularly impacted in DS and where consequently the majority of cellular and neuronal network research has been performed using DS animal models, in particular the Ts65Dn mouse. Finally, we will postulate on how altered plasticity may contribute to the DS cognitive disability.

scholarly journals Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome

2006 ◽  
Vol 99 (4) ◽  
pp. 1320-1320 ◽  
Author(s):  
Richard J. Siarey ◽  
Angelina Kline-Burgess ◽  
Madelaine Cho ◽  
Andrea Balbo ◽  
Tyler K. Best ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Signaling Pathways ◽  
Ts65dn Mouse ◽  
Hippocampal Synaptic Plasticity

scholarly journals Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome

2006 ◽  
Vol 98 (4) ◽  
pp. 1266-1277 ◽  
Author(s):  
Richard J. Siarey ◽  
Angelina Kline-Burgess ◽  
Madelaine Cho ◽  
Andrea Balbo ◽  
Tyler K. Best ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Signaling Pathways ◽  
Ts65dn Mouse ◽  
Hippocampal Synaptic Plasticity

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 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.

scholarly journals Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Han-Chung Lee ◽  
Kai-Leng Tan ◽  
Pike-See Cheah ◽  
King-Hwa Ling
Keyword(s):  
Down Syndrome ◽  
Brain Development ◽  
Cell Fate ◽  
Mouse Models ◽  
Neuronal Cell ◽  
Janus Kinase ◽  
Chromosome 21 ◽  
Severe Intellectual Disability ◽  
Stat Signaling

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.

scholarly journals Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome

2019 ◽  
Author(s):  
Shruti Jain ◽  
Christina A. Watts ◽  
Wilson C.J. Chung ◽  
Kristy Welshhans
Keyword(s):  
Down Syndrome ◽  
Corpus Callosum ◽  
Mouse Model ◽  
Hippocampal Neurons ◽  
Anterior Commissure ◽  
Axon Growth ◽  
Chromosome 21 ◽  
Ts65dn Mouse ◽  
Hippocampal Commissure ◽  
Interhemispheric Connectivity

AbstractDown syndrome is the most common genetic cause of intellectual disability and occurs due to the trisomy of human chromosome 21. Adolescent and adult brains from humans with Down syndrome exhibit various neurological phenotypes including a reduction in the size of the corpus callosum, hippocampal commissure and anterior commissure. However, it is unclear when and how these interhemispheric connectivity defects arise. Using the Ts65Dn mouse model of Down syndrome, we examined interhemispheric connectivity in postnatal day 0 (P0) Ts65Dn mouse brains. We find that there is no change in the volume of the corpus callosum or anterior commissure in P0 Ts65Dn mice. However, the volume of the hippocampal commissure is significantly reduced in P0 Ts65Dn mice, and this may contribute to the impaired learning and memory phenotype of this disorder. Interhemispheric connectivity defects that arise during development may be due to disrupted axon growth. In line with this, we find that developing hippocampal neurons display reduced axon length in vitro, as compared to neurons from their euploid littermates. This study is the first to report the presence of defective interhemispheric connectivity at the time of birth in Ts65Dn mice, providing evidence that early therapeutic intervention may be an effective time window for the treatment of Down syndrome.

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 Potassium channel regulators are differentially expressed in hippocampi of Ts65Dn and Tc1 Down syndrome mouse models

2018 ◽  
Author(s):  
Shani Stern ◽  
Rinat Keren ◽  
Yongsung Kim ◽  
Elisha Moses
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Potassium Channel ◽  
Mouse Models ◽  
Chromosome 21 ◽  
Neuronal Cultures ◽  
Rna Expression ◽  
Genetic Changes ◽  
Expression Levels ◽  
Whole Cell Patch Clamp

AbstractBackground:Down syndrome remains the main genetic cause of intellectual disability, with an incidence rate of about 1 in 700 live births. The Ts65Dn mouse strain, with an extra murine chromosome that includes genes from chromosomes 10, 16 and 17 of the mouse and the Tc1 strain with an extra human chromosome 21, are currently accepted as informative and well-studied models for Down Syndrome. Using whole cell patch clamp we recently showed changes in several types of transmembrane currents in hippocampal neuronal cultures of Ts65Dn and Tc1 embryos. The associated genetic changes responsible for these changes in physiology were yet to be studied.Methods:We used qPCR to measure RNA expression level of a few of the channel genes that we suspect are implicated in the previously reported changes of measured currents, and performed statistical analysis using Matlab procedures for the standard t-test and ANOVA and for calculating correlations between the RNA expression levels of several channel genes.Results:We present differential gene expression levels measured using qPCR of the potassium channel regulators KCNE1 and KCNE2 in both Ts65Dn and Tc1 embryos and pups compared to controls. In Tc1, the human genes KCNJ6 and KCNJ15 are expressed in addition to a statistically insignificant increase of expression in the mouse genes KCNJ6 and KCNJ15. All channel genes that we have measured with large replication, have the same up-regulation or down-regulation in both mouse models, indicating that the transcription mechanism acts similarly in these two mouse models. The large dataset furthermore allows us to observe correlations between different channel genes. We find that, despite the significant changes in expression levels, channels that are known to interact have a high and significant correlation in expression both in controls and in the Down syndrome mouse model.Conclusions:We suggest the differential expression of KCNE1 and KCNE2 as a possible cause for our previously reported changes in potassium currents. We report a KCNJ6 and KCNJ15 overexpression, which plays a role in the increased input conductance and the reduced cell excitability that we previously reported in the Tc1 mouse model. The large and significant positive (KCNQ2-KCNQ3, KCNE1-KCNE2, KCNQ3-KCNE1, KCNQ2-KCNE1, KCNQ2-KCNE2, KCNQ3-KCNE2) and negative correlations (KCNE1-KCNJ15, KCNE2-KCNJ15) that we find between channel genes indicate that these genes probably work in a cooperative or in a mutually exclusive manner.

scholarly journals Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 767-775 ◽  
Author(s):  
Gina Kirsammer ◽  
Sarah Jilani ◽  
Hui Liu ◽  
Elizabeth Davis ◽  
Sandeep Gurbuxani ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Gene Dosage ◽  
Hematologic Malignancies ◽  
Chromosome 21 ◽  
Myeloproliferative Disease ◽  
Ts65dn Mouse ◽  
Hematopoietic Stem ◽  
Megakaryoblastic Leukemia ◽  
Increased Risk

Children with Down syndrome (DS) display macrocytosis, thrombocytosis, and a 500-fold increased risk of developing megakaryocytic leukemia; however, the specific effects of trisomy 21 on hematopoiesis remain poorly defined. To study this question, we analyzed blood cell development in the Ts65Dn mouse model of DS. Ts65Dn mice are trisomic for 104 orthologs of Hsa21 genes and are the most widely used mouse model for DS. We discovered that Ts65Dn mice display persistent macrocytosis and develop a myeloproliferative disease (MPD) characterized by profound thrombocytosis, megakaryocyte hyperplasia, dysplastic megakaryocyte morphology, and myelofibrosis. In addition, these animals bear distorted hematopoietic stem and myeloid progenitor cell compartments compared with euploid control littermates. Of the 104 trisomic genes in Ts65Dn mice, Aml1/Runx1 attracts considerable attention as a candidate oncogene in DS–acute megakaryoblastic leukemia (DS-AMKL). To determine whether trisomy for Aml1/Runx1 is essential for MPD, we restored disomy at the Aml1/Runx1 locus in the Ts65Dn strain. Surprisingly, trisomy for Aml1/Runx1 is not required for megakaryocyte hyperplasia and myelofibrosis, suggesting that trisomy for one or more of the remaining genes can promote this disease. Our studies demonstrate the potential of DS mouse models to improve our understanding of chromosome 21 gene dosage effects in human hematologic malignancies.

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