De Toma, I. | Search bioRxiv

bioRxiv2021

Single nucleus RNA-seq in the hippocampus of a Down syndrome mouse model reveals new key players in memory

Down syndrome (DS) is the most common genetic cause of intellectual disability. Even though great advances in the last decades have allowed better delineation of its pathogenetic mechanisms, its cellular and molecular bases are still poorly understood. To evaluate the consequences of chromosome aneuploidy on the hippocampus, we analyzed single-nucleus transcriptional profiles of the DS mouse model Ts65Dn. Our data revealed abnormal cell composition specifically of the Ts65Dn dentate gyrus and of specific subtypes of interneurons, without major changes in CA1 or CA3. We found that trisomy results in a highly cell-type specific global alteration of the transcriptome and detected previously undefined differentially expressed genes in specific neuronal populations. We identified the long-non-coding gene Snhg11 to be specifically downregulated in the trisomic dentate gyrus and provide evidence for its involvement in hippocampal-dependent cognitive phenotypes, possibly contributed by impaired adult neurogenesis.

neuroscience↗

bioRxiv2020

Characterization of the microbiome of Down syndrome mouse model (Ts65Dn) in standard and high-fat diet.

The intestinal microbiota is known to affect its host in numerous ways and can be altered by many factors including the host genotype and high-calorie diets. Down syndrome (DS) is a genetic neurodevelopmental disorder caused by the total or partial triplication of chromosome 21. Recently, a human study reported microbiota differences between DS and euploid humans. To further explore the differences due to the genotype, we here investigated the microbiome of trisomic mice (Ts65Dn). In trisomic mice we found a significant enrichment in abundances of bacteria: Bacteroides ovatus, B. thetaiotaomicron, and Akkermansia muciniphila - the mucus-degrading and gut-health promoting species. Since diet composition has an effect on microbiota species, we studied the effect of a high-fat diet on the observed genotypic differences. Our study provides evidence that microbiomes of trisomic mice on the control diet present more inter-individual differences than WT mice. Moreover, we observed that the high-fat diet led to increased differences between individuals and this effect was even more pronounced in the trisomic than in WT mice. We validated the results obtained with widely used 16rRNA gene sequencing with the sequencing of the total RNA. HighlightsO_LIDown syndrome (DS) model mice faecal microbiomes are characterized by an overrepresentation of Bacteroides ovatus, Bacteroides thetaiotaomicron, and Akkermansia muciniphila species. C_LIO_LIDS mice are characterized by higher heterogeneity of their microbiome communities than WT mice. C_LIO_LIHigh-fat diet leads to more diverse microbiome communities between mice, especially in trisomic genotype. C_LI

genomics↗