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

Chang, Pishan; Bush, Daniel; Schorge, Stephanie; Good, Mark Andrew; Canonica, Tara; Shing, Nathanael; S, Noy; Wiseman, Frances K.; Burgess, Neil; Tybulewicz, Victor L. J.; Walker, Matthew C.; Fisher, Elizabeth

doi:10.1016/j.celrep.2019.12.065

Cited by 41 publications

(42 citation statements)

References 87 publications

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“…The overall LFP power spectra observed in mPFC is similar in both Ts and Eu mice, consistently with a recent report (Chang et al, 2020). However, close examination of stLFP revealed a strong increase in the power of β-and low γ-frequency bands during periods of spiking activity.…”

Section: Discussionsupporting

confidence: 91%

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Martín

Donato

Peixoto

et al. 2020

eLife

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Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS.

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Section: Discussionsupporting

confidence: 91%

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Martín

Donato

Peixoto

et al. 2020

eLife

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“…The minimal common genetic part of these lines was the overexpression of Dyrk1a and the result observed for transgenic Tg(Dyrk1a). Altogether, our previous results support DYRK1A as being the main driver of working memory defect (25) although another region could be involved in controlling spontaneous alternation (42).…”

Section: Discussionsupporting

confidence: 71%

“…Dp5/Dp1 also showed a clear deficit in the percentage of spontaneous alternation in comparison to littermate controls while Dp5Yah trisomic animals showed normal performance. Thus the overexpression of Dyrk1a alone was sufficient to mimic the Y maze spontaneous alternation found in 3 overlapping DS models but we cannot rule out the possibility that another region is involved, as suggested by the work of Chang et al (42).…”

Section: Dissecting the Contribution Of Mmu16 Subregions To Ds-related Behavioral Phenotypes In Mouse Modelsmentioning

confidence: 74%

Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models

Hérault

Duchon

Moreno

et al. 2020

Preprint

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AbstractDown syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype–phenotype correlations, we screened the in vivo DS mouse library with standardized behavioural tests, magnetic resonance imaging (MRI) and digged into hippocampal gene expression. Altogether this approach brings novel insights into the field. First, we unravelled genetic interactions between different regions of the chromosome 21 and how they importantly contribute in altering the outcome of the phenotypes. Then, in depth analysis of misregulated expressed genes involved in synaptic dysfunction highlitghed 6 biological cascades centered around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to advance in our understanding of DS and therapies development.Author SummaryDown syndrome (DS) is the most frequent cause of intellectual disability and is caused by increase in gene dosage and multiple genetic interaction but not so many have been described so far. Taking advantage of DS mouse models, we investigated behavior and cognition, brain morphology and hippocampal gene expression in a controlled environment and we unraveled how multiple genetic interactions between different regions of the chromosome 21 contribute in altering the outcome of the behavioural, morphological and molecular/pathways phenotypes. Nonetheless we found multiple deregulated genes in the hippocampus, where overlapping DS models show convergence in the biological cascades altered, observed via building protein-protein interaction and regulatory networks, and centered in 6 main hubs: DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Although four of them were already described to be altered in some DS models, we validated two additional ones, RHOA and NPAS4, and we have built a novel vision of the existing altered gene-gene crosstalk and molecular mechanisms, targeting 6 specific highly interconnected hubs in DS models, that should become central to advance in our understanding of DS physiopathology and therapy development.

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“…Thus, the overexpression of Dyrk1a alone was sufficient to mimic the Y-maze spontaneous alternation found in three overlapping DS models but we cannot rule out the possibility that another region is involved, as suggested by the work of Chang et al . ( 41 ).…”

Section: Resultsmentioning

confidence: 99%

Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models

Duchon

Moreno

Lorenzo

et al. 2021

Human Molecular Genetics

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Down syndrome (DS) is the most common genetic form of intellectual disability caused by the presence of an additional copy of human chromosome 21 (Hsa21). To provide novel insights into genotype–phenotype correlations, we used standardized behavioural tests, magnetic resonance imaging (MRI) and hippocampal gene expression to screen several DS mouse models for the mouse chromosome 16 region homologous to Hsa21. First, we unravelled several genetic interactions between different regions of chromosome 21 and how they contribute significantly to altering the outcome of the phenotypes in brain cognition, function and structure. Then, in-depth analysis of misregulated expressed genes involved in synaptic dysfunction highlighted 6 biological cascades centred around DYRK1A, GSK3β, NPY, SNARE, RHOA and NPAS4. Finally, we provide a novel vision of the existing altered gene–gene crosstalk and molecular mechanisms targeting specific hubs in DS models that should become central to better understanding of DS and improving the development of therapies.

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

Cited by 41 publications

References 87 publications

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models

Multi-influential genetic interactions alter behaviour and cognition through six main biological cascades in Down syndrome mouse models

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