Early appearance of dendritic alterations in neocortical pyramidal neurons of the Ts65Dn model of Down syndrome

Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS. While neurogenesis impairment in DS is a fetal event, dendritic pathology occurs after the first postnatal months. Neurogenesis alterations across the lifespan have been extensively studied in the Ts65Dn mouse. In contrast, there is scarce information regarding dendritic alterations at early life stages in this and other models, although there is evidence for dendritic alterations in adult mouse models. Thus, the goal of the current study was to establish whether dendritic alterations are already present in the neonatal period in Ts65Dn mice. In Golgi-stained brains we quantified the dendritic arbors of layer II/III pyramidal neurons in the frontal cortex of Ts65Dn mice aged 2 (P2) and 8 (P8) days and their euploid littermates. In P2 Ts65Dn mice we found a moderate hypotrophy of the apical and collateral dendrites but a patent hypotrophy of the basal dendrites. In P8 Ts65Dn mice the distalmost apical branches were missing or reduced in number but there were no alterations in the collateral and basal dendrites. No genotype effects were detected on either somatic or dendritic spine density. This study shows dendritic branching defects that mainly involve the basal domain in P2 Ts65Dn mice, and the apical but not the other domains in P8 Ts65Dn mice. This suggests that dendritic defects may be related to dendritic compartment and age. The lack of a severe dendritic pathology in Ts65Dn pups is reminiscent of the delayed appearance of patent dendritic alterations in newborns with DS. This similarly highlights the usefulness of the Ts65Dn model for the study of the mechanisms underlying dendritic alterations in DS and the design of possible therapeutic interventions.

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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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Early Sensory Loss Alters the Dendritic Branching and Spine Density of Supragranular Pyramidal Neurons in Rodent Primary Sensory Cortices

Frontiers in Neural Circuits ◽

10.3389/fncir.2019.00061 ◽

2019 ◽

Vol 13 ◽

Author(s):

Tamar Macharadze ◽

Eike Budinger ◽

Michael Brosch ◽

Henning Scheich ◽

Frank W. Ohl ◽

...

Keyword(s):

Pyramidal Neurons ◽

Sensory Loss ◽

Spine Density ◽

Dendritic Branching ◽

Sensory Cortices

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Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome

10.1101/784314 ◽

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.

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Alterations of in vivo CA1 network activity in Dp(16)1Yey Down syndrome model mice

eLife ◽

10.7554/elife.31543 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 6

Author(s):

Matthieu Raveau ◽

Denis Polygalov ◽

Roman Boehringer ◽

Kenji Amano ◽

Kazuhiro Yamakawa ◽

...

Keyword(s):

Down Syndrome ◽

Pyramidal Neurons ◽

Chromosome 21 ◽

Network Activity ◽

Inhibitory Neurons ◽

Spatial Coding ◽

Extra Copy ◽

Hippocampal Ca1

Down syndrome, the leading genetic cause of intellectual disability, results from an extra-copy of chromosome 21. Mice engineered to model this aneuploidy exhibit Down syndrome-like memory deficits in spatial and contextual tasks. While abnormal neuronal function has been identified in these models, most studies have relied on in vitro measures. Here, using in vivo recording in the Dp(16)1Yey model, we find alterations in the organization of spiking of hippocampal CA1 pyramidal neurons, including deficits in the generation of complex spikes. These changes lead to poorer spatial coding during exploration and less coordinated activity during sharp-wave ripples, events involved in memory consolidation. Further, the density of CA1 inhibitory neurons expressing neuropeptide Y, a population key for the generation of pyramidal cell bursts, were significantly increased in Dp(16)1Yey mice. Our data refine the ‘over-suppression’ theory of Down syndrome pathophysiology and suggest specific neuronal subtypes involved in hippocampal dysfunction in these model mice.

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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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Distinct properties of layer 3 pyramidal neurons from prefrontal and parietal areas of the monkey neocortex

10.1101/649228 ◽

2019 ◽

Author(s):

Guillermo Gonzalez-Burgos ◽

Takeaki Miyamae ◽

Yosef Krimer ◽

Yelena Gulchina ◽

Diego Pafundo ◽

...

Keyword(s):

Working Memory ◽

Parietal Cortex ◽

Posterior Parietal Cortex ◽

Pyramidal Neurons ◽

Spine Density ◽

Cortical Areas ◽

Basal Dendrites ◽

Dorsolateral Prefrontal ◽

Posterior Parietal ◽

Memory Network

AbstractIn primates, working memory function depends on activity in a distributed network of cortical areas that display different patterns of delay task-related activity. These differences are correlated with, and might depend on, distinctive properties of the neurons located in each area. For example, layer 3 pyramidal neurons (L3PNs) differ significantly between primary visual and dorsolateral prefrontal (DLPFC) cortices. However, to what extent L3PNs differ between DLPFC and other association cortical areas is less clear. Hence, we compared the properties of L3PNs in monkey DLPFC versus posterior parietal cortex (PPC), a key node in the cortical working memory network. Using patch clamp recordings and biocytin cell filling in acute brain slices, we assessed the physiology and morphology of L3PNs from monkey DLPFC and PPC. The L3PN transcriptome was studied using laser microdissection combined with DNA microarray or quantitative PCR. We found that in both DLPFC and PPC, L3PNs were divided into regular spiking (RS-L3PNs) and bursting (B-L3PNs) physiological subtypes. Whereas regional differences in single-cell excitability were modest, B-L3PNs were rare in PPC (RS-L3PN:B-L3PN, 94:6), but were abundant in DLPFC (50:50), showing greater physiological diversity. Moreover, DLPFC L3PNs display larger and more complex basal dendrites with higher dendritic spine density. Additionally, we found differential expression of hundreds of genes, suggesting a transcriptional basis for the differences in L3PN phenotype between DLPFC and PPC. These data show that the previously observed differences between DLPFC and PPC neuron activity during working memory tasks are associated with diversity in the cellular/molecular properties of L3PNs.Significance statementIn the human and non-human primate neocortex, layer 3 pyramidal neurons (L3PNs) differ significantly between dorsolateral prefrontal (DLPFC) and sensory areas. Hence, L3PN properties reflect, and may contribute to, a greater complexity of computations performed in DLPFC. However, across association cortical areas, L3PN properties are largely unexplored. We studied the physiology, dendrite morphology and transcriptome of L3PNs from macaque monkey DLPFC and posterior parietal cortex (PPC), two key nodes in the cortical working memory network. L3PNs from DLPFC had greater diversity of physiological properties and larger basal dendrites with higher spine density. Moreover, transcriptome analysis suggested a molecular basis for the differences in the physiological and morphological phenotypes of L3PNs from DLPFC and PPC.

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

Neural Plasticity ◽

10.1155/2012/101542 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 22

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.

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