Enhancing sleep after training improves memory in Down syndrome model mice

SLEEP ◽  
2021 ◽  
Author(s):  
E Pittaras ◽  
D Colas ◽  
B Chuluun ◽  
G Allocca ◽  
C Heller
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Spatial Memory ◽  
Cognitive Disabilities ◽  
Genetic Disorder ◽  
Memory Task ◽  
Nrem Sleep ◽  
Chromosome 21 ◽  
Knowing That ◽  
Behavioral Method

Abstract Down syndrome (DS) is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. DS is associated with cognitive disabilities, for which there are no drug therapies. In spite of significant behavioral and pharmacological efforts to treat cognitive disabilities, new and continued efforts are still necessary. Over sixty percent of children with DS are reported to have sleep apnea that disrupt normal sleep. Normal and adequate sleep is necessary to maintain optimal cognitive functions. Therefore, we asked whether improved quality and/or quantity of sleep could improve cognitive capacities of people with DS. To investigate this possibility, we used the Ts65Dn mouse model of DS and applied two methods for enhancing their sleep following training on mouse memory tasks. A behavioral method was to impose sleep deprivation prior to training resulting in sleep rebound following the training. A pharmacologic method, hypocretin receptor 2 antagonist, was used immediately after the training to enhance subsequent sleep knowing that hypocretin is involved in the maintenance of wake. Our behavioral method resulted in a sleep reorganization that decreased wake and increased REM sleep following the training associated with an improvement of recognition memory and spatial memory in the DS model mice. Our pharmacologic approach decreased wake and increased NREM sleep and was associated with improvement only in the spatial memory task. These results show that enhancing sleep after the training in a memory task improves memory consolidation in a mouse model of DS.

Ts65Dn, a Mouse Model of Down Syndrome, Exhibits Increased GABAB-Induced Potassium Current

2007 ◽  
Vol 97 (1) ◽  
pp. 892-900 ◽  
Author(s):  
Tyler K. Best ◽  
Richard J. Siarey ◽  
Zygmunt Galdzicki
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Hippocampal Neurons ◽  
Single Channel ◽  
Extra Chromosome ◽  
Functional Expression ◽  
Chromosome 21 ◽  
Fluctuation Analysis ◽  
Response Curves ◽  
Girk Channel

Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein-coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus. Here we report that this overexpression leads to a significant increase (∼2-fold) in GABAB-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady-state GIRK current density is significantly shifted left toward lower concentrations of baclofen in Ts65Dn neurons compared with diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single-channel conductance compared with diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggests unimpaired mechanisms of interaction between GIRK channel and GABAB receptor. These results indicate that increased expression of GIRK2 containing channels have functional consequences that likely affect the balance between excitatory and inhibitory neuronal transmission.

scholarly journals Gambaran Erupsi Gigi Permanen pada Anak Sindrom Down Usia 10-16 Tahun di Sekolah Luar Biasa Kabupaten Jember

2018 ◽  
Vol 8 (1) ◽  
pp. 8
Author(s):  
Loly Anastasya Sinaga ◽  
Dwi Kartika Apriyono ◽  
Masniari Novita
Keyword(s):  
Down Syndrome ◽  
Special Needs ◽  
Physical Characteristic ◽  
Trisomy 21 ◽  
Genetic Disorder ◽  
Extra Chromosome ◽  
Descriptive Study ◽  
Chromosome 21 ◽  
Permanent Teeth ◽  
Intellectual Abilities

Background: Down Syndrome is a genetic disorder that occurs because of chromosome 21 has three chromosome (trisomy 21). The extra chromosome changes the genetic balance, physical characteristic, intellectual abilities, and physiological body function. Tooth eruption in Down Syndrome children typically delayed in both the timing and sequence of eruption up to two or three years. Objective: To observe the permanent teeth eruption in Down syndrome children at age 10-16 years old, boys and girls in Special Needs School in Jember. Materials and Methods: This research was a descriptive study with 7 subjects. Each subject was examined then calculated teeth that had emerged or functionally eruption with articualting paper. Result and Conclusion:  Both permanent teeth that is still partially erupted tooth (emerged/ EM) and had erupted perfectly (functionally eruption/ FE) delayed in eruption in Down Syndrome boys and girls at age 10-16 years old.

scholarly journals The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

2020 ◽  
Vol 29 (12) ◽  
pp. 1950-1968
Author(s):  
Charlotte Castillon ◽  
Laurine Gonzalez ◽  
Florence Domenichini ◽  
Sandrine Guyon ◽  
Kevin Da Silva ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Spatial Memory ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
Memory Task ◽  
Clinical Signs ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

A Myeloproliferative Disorder in the Tc1 Mouse Model of Down Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2790-2790
Author(s):  
Kate A. Alford ◽  
Lesley Vanes ◽  
Zhe Li ◽  
Stuart H. Orkin ◽  
Elizabeth M. C. Fisher ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Extramedullary Hematopoiesis ◽  
Myeloproliferative Disorder ◽  
Chromosome 21 ◽  
Gene Encoding ◽  
Megakaryoblastic Leukemia ◽  
Cell Counts ◽  
Hematopoietic Disorders

Abstract Down syndrome (DS) children have a one in ten chance of being diagnosed with leukemia within the first ten years of life. Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) that accounts for nearly 50% of these leukemias. AMKL is associated with a self-regressing neoplasia found almost exclusively in DS newborns called Transient Myeloproliferative Disorder (TMD). In all cases of TMD and DS-AMKL, leukemic blast cells show mutations in the gene encoding the hematopoietic transcription factor GATA1, resulting in production of a truncated form of the protein called GATA1s. Mutations in GATA1 are not seen in non-DS-AMKL or other DS leukemias and it is clear both trisomy of human chromosome 21 (HSA21) and a mutation in GATA1 are required for the development of both TMD and AMKL. However, it is unknown which genes on HSA21 need to be trisomic in order to predispose an individual with DS to AMKL. Our group has generated mice (termed the Tc1 mice) that contain an almost complete, freely segregating copy of HSA21. These mice display phenotypic features of DS. We have examined adult hematopoiesis in these mice. Blood samples taken from a cohort of Tc1 mice were examined from 4 weeks until 60 weeks of age. Complete blood cell counts show that whilst the mice do not develop leukemia they displayed persistent macrocytosis and had reduced erythrocyte numbers. Crossing the Tc1 mice with mice that express GATA1s protein did not perturb or exacerbate this phenotype. Over the age of 15 months more than 50% of Tc1 mice examined were found to have developed splenomegaly. These mice displayed megakaryocyte hyperplasia and had increased numbers of cells of the erythroid lineage. In vitro colony forming assays demonstrated an increase in the frequency of megakaryocytic and granulocyte-macrophage progenitors in the spleen, consistent with extramedullary hematopoiesis. In the bone marrow, no abnormalities were seen in the lineage-, c-Kit+, Sca1+ (LSK) compartment, however there was a significant increase in the percentage of common myeloid progenitors (CMP) and a corresponding decrease in megakaryocyte-erythrocyte progenitors (MEP). This suggests a possible block in development from CMP to MEP. These data demonstrate defects in hematopoietic development in a proportion of adult Tc1 mice. However, preliminary data suggest that these mice do not develop a neonatal myeloproliferative disorder that is comparable with human TMD. It may be that the phenotype seen in the adult Tc1 mice is due to defects in hematopoietic progenitors that are different to those responsible for development of TMD and DS-AMKL. This mouse model may therefore provide a useful tool to examine the role of HSA21 genes in adult hematopoietic disorders.

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 Bioinformatics Investigation and Contribution of Other Chromosomes Besides Chromosome 21 in the Risk of Down Syndrome Development

2021 ◽  
Vol 12 (1) ◽  
pp. 79-88
Author(s):  
Mona Zamanian Azodi ◽  
◽  
Mostafa Rezaei Tavirani ◽  
Majid Rezaei Tavirani ◽  
Mohammad Rostami Nejad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Gene Expression Profile ◽  
Clinical Studies ◽  
Genetic Disorder ◽  
Research Topic ◽  
Chromosome 21 ◽  
Network Centrality ◽  
Microarray Study ◽  
Molecular Studies

Introduction: Down syndrome as a genetic disorder is a popular research topic in molecular studies. One way to study Down syndrome is via bioinformatics. Methods: In this study, a gene expression profile from a microarray study was selected for more investigation. Results: The study of Down syndrome patients shows specific genes with differential expression and network centrality properties. These genes are introduced as RHOA, FGF2, FYN, and CD44, and their level of expression is high in these patients. Conclusion: This study suggests that besides chromosomes 21, there are additional contributing chromosomes to the risk of Down syndrome development. Besides, these genes could be used for clinical studies after more analysis.

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 Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome

2021 ◽  
Vol 14 (11) ◽  
pp. 1170
Author(s):  
Wenche Stensen ◽  
Ulli Rothweiler ◽  
Richard Alan Engh ◽  
Melissa R. Stasko ◽  
Ilya Bederman ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Cognitive Deficits ◽  
Genetic Disorder ◽  
Treatment Options ◽  
Chromosome 21 ◽  
The Novel ◽  
Behavioral Challenges ◽  
Early Onset Alzheimer’S Disease ◽  
Encoding Gene ◽  
Complex Genetic Disorder

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer’s disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research.

Down Syndrome from a Neurodevelopmental Perspective

2016 ◽  
Author(s):  
Hana D’Souza ◽  
Jamie Edgin ◽  
Annette Karmiloff-Smith
Keyword(s):  
Down Syndrome ◽  
Individual Differences ◽  
Trisomy 21 ◽  
Genetic Disorder ◽  
Developmental Time ◽  
Receptive Vocabulary ◽  
Chromosome 21 ◽  
Typically Developing ◽  
Altered Expression ◽  
Wide Range

This is an advance summary of a forthcoming article in the Oxford Research Encyclopedia of Psychology. Please check back later for the full article. Down syndrome (DS; trisomy 21) is the most common genetic disorder associated with intellectual disability. It occurs in one out of every 700 to 1,000 live births. DS is caused by trisomy of human chromosome 21, which results in the altered expression of over 300 genes. This neurodevelopmental syndrome is characterized by distinctive facial dysmorphology and an uneven cognitive phenotype including relative strengths and weaknesses. Relative strengths include visual processing, receptive vocabulary, and social-emotional functioning (though performance in these domains generally falls below the level expected for typically developing individuals). Relative weaknesses include verbal working memory, expressive language, and motor ability. However, the phenotype of individuals with DS is far from homogeneous, and a wide range of individual differences is present at every level of description. On the genetic level, the trisomy can occur through different mechanisms at distinct developmental time points, and the expression of trisomy 21 may be modulated by different genes across individuals. On the level of the brain, individual differences in brain structure and/or function correlate with variation in cognition and behavior, including communication skills. Large individual differences can also be observed on the cognitive level. For example, while some toddlers with DS are nonverbal, others reach expressive vocabulary levels close to those of typically developing children. A wide range of individual differences has also been reported in other areas, including the motor domain, sleep, parent-child interaction, and medical and psychiatric comorbidities. In order to understand a neurodevelopmental syndrome such as DS, it is crucial to consider individual variations at multiple levels of description and the interactions between them over developmental time. A more complex, dynamic view that goes beyond a description of DS as a homogenous group is thus required.

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