Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome

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.

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

Journal of Neurophysiology ◽

10.1152/jn.00626.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 892-900 ◽

Cited By ~ 74

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.

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

Blood ◽

10.1182/blood-2007-04-085670 ◽

2008 ◽

Vol 111 (2) ◽

pp. 767-775 ◽

Cited By ~ 68

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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Adult-Onset Fluoxetine Treatment Does Not Improve Behavioral Impairments and May Have Adverse Effects on the Ts65Dn Mouse Model of Down Syndrome

Neural Plasticity ◽

10.1155/2012/467251 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 24

Author(s):

Markus Heinen ◽

Moritz M. Hettich ◽

Devon P. Ryan ◽

Susanne Schnell ◽

Katharina Paesler ◽

...

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Chromosome 21 ◽

Adult Onset ◽

Ts65dn Mouse ◽

Receptor Antagonists ◽

Memory Impairments ◽

Severe Intellectual Disability ◽

Fluoxetine Treatment ◽

Behavioral Impairments

Down syndrome is caused by triplication of chromosome 21 and is associated with neurocognitive phenotypes ranging from severe intellectual disability to various patterns of more selective neuropsychological deficits, including memory impairments. In the Ts65Dn mouse model of Down syndrome, excessive GABAergic neurotransmission results in local over-inhibition of hippocampal circuits, which dampens hippocampal synaptic plasticity and contributes to cognitive impairments. Treatments with several GABAAreceptor antagonists result in increased plasticity and improved memory deficits in Ts65Dn mice. These GABAAreceptor antagonists are, however, not suitable for clinical applications. The selective serotonin reuptake inhibitor fluoxetine, in contrast, is a widely prescribed antidepressant that can also enhance plasticity in the adult rodent brain by lowering GABAergic inhibition. For these reasons, we wondered if an adult-onset 4-week oral fluoxetine treatment restores spatial learning and memory impairments in Ts65Dn mice. Fluoxetine did not measurably improve behavioral impairments of Ts65Dn mice. On the contrary, we observed seizures and mortality in fluoxetine-treated Ts65Dn mice, raising the possibility of a drug × genotype interaction with respect to these adverse treatment outcomes. Future studies should re-address this in larger animal cohorts and determine if fluoxetine treatment is associated with adverse treatment effects in individuals with Down syndrome.

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Disordered phasic relationships between hippocampal place cells, theta, and gamma rhythms in the Ts65Dn mouse model of Down Syndrome

10.1101/2020.09.17.301432 ◽

2020 ◽

Author(s):

H.C. Heller ◽

A. Freeburn ◽

D.P. Finn ◽

R.G.K Munn

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Learning And Memory ◽

Medial Septum ◽

Place Cells ◽

Chromosome 21 ◽

Ts65dn Mouse ◽

Gamma Rhythms ◽

Relationship Of

AbstractDown Syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS have shown changes in spectral coherence in the field potentials of hippocampus and regions important for executive function such as prefrontal cortex. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from Medial Septum (MS) to regions such as hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in the Ts65Dn mouse model of DS in comparison to their non-trisomic 2N littermates. We find changes in hippocampal phenomenology that suggest that MS output, which drives theta rhythm in the hippocampus, is strongly altered. Moreover, we find that this change affects the phasic relationship of both CA1 place cells and gamma rhythms to theta. Since the phasic relationship of both of these aspects of hippocampal phenomenology to theta are thought to be critical for the segregation of encoding and retrieval epochs within hippocampus, it is likely that these changes are the neural substrates of the learning and memory deficits seen both in human DS and animal models such as Ts65Dn.

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Faculty Opinions recommendation of Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022994.264742 ◽

2004 ◽

Author(s):

Carol Mason

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Ts65dn Mouse ◽

Structural Abnormalities

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Long-term voluntary running modifies the levels of proteins of the excitatory/inhibitory system and reduces reactive astrogliosis in the brain of Ts65Dn mouse model for Down syndrome

Brain Research ◽

10.1016/j.brainres.2021.147535 ◽

2021 ◽

pp. 147535

Author(s):

Elizabeth Kida ◽

Marius Walus ◽

Giorgio Albertini ◽

Adam A. Golabek

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Ts65dn Mouse ◽

Inhibitory System ◽

Reactive Astrogliosis ◽

Voluntary Running ◽

The Brain

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Increased excitability and altered action potential waveform in cerebellar granule neurons of the Ts65Dn mouse model of Down syndrome

Brain Research ◽

10.1016/j.brainres.2012.05.027 ◽

2012 ◽

Vol 1465 ◽

pp. 10-17 ◽

Cited By ~ 8

Author(s):

Maria M. Usowicz ◽

Claire L.P. Garden

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Action Potential ◽

Cerebellar Granule Neurons ◽

Granule Neurons ◽

Ts65dn Mouse ◽

Cerebellar Granule ◽

Action Potential Waveform ◽

Potential Waveform

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Behavioral validation of the Ts65Dn mouse model for Down syndrome of a genetic background free of the retinal degeneration mutation Pde6brd1

Behavioural Brain Research ◽

10.1016/j.bbr.2009.08.034 ◽

2010 ◽

Vol 206 (1) ◽

pp. 52-62 ◽

Cited By ~ 48

Author(s):

Alberto C.S. Costa ◽

Melissa R. Stasko ◽

Cecilia Schmidt ◽

Muriel T. Davisson

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Retinal Degeneration ◽

Genetic Background ◽

Ts65dn Mouse ◽

Behavioral Validation

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Of mice and Down syndrome

Blood ◽

10.1182/blood-2007-10-116061 ◽

2008 ◽

Vol 111 (2) ◽

pp. 472-472 ◽

Cited By ~ 1

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.

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