Biology subjects

Dierssen, M.

Publications and source records attributed to Dierssen, M..

12 recordsLinked to original sources

bioRxiv2026

HDAC inhibitor treatment restores transcriptome, chromatin accessibility and memory deficits in a mouse model for Down syndrome

Down syndrome (DS) is associated with widespread molecular alterations, including aberrant gene expression, which not only affects chromosome 21 genes but perturbs the whole transcriptome. The genome-wide nature of this alteration suggests that it might be epigenetically mediated, which may also offer therapeutic opportunities given the reversibility of epigenetic modifications. Here, we show that decreased global acetylation level in the hippocampus of the trisomic mouse model Ts65Dn is associated with decreased chromatin accessibility at gene promoters in hippocampal neurons. Strikingly, pharmacological restoration of histone acetylation using the clinically approved histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) normalized transcriptomic, epigenetic and cortico-hippocampal memory deficits in trisomic mice. This rescue was mediated by an unexpected heterochromatization of the supernumerary chromosome. Altogether, our results identify an unanticipated epigenetic mechanism linking histone acetylation dynamics to chromosomal dosage homeostasis.

molecular biology↗

bioRxiv2024

Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations

Cognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity ([~]40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders. Author summaryThe structural integrity of individual brain neurons and the intricate networks they form are fundamental to all brain functions, with structural anomalies directly linked to neurological disorders. Deciphering these links is a leading question in developmental disorders such as Down syndrome. Our work sheds light on the pivotal role that the structure of complex neural systems plays in shaping emergent network activity. In particular, our anatomically informed network modeling enables determining the extent to which specific deficits in neuronal architecture and connectivity perturb oscillatory patterns of activity.

neuroscience↗

bioRxiv2023

Deficits in neuronal architecture but not over-inhibition are main determinants of reduced neuronal network activity in a mouse model of overexpression of Dyrk1A

Abnormal dendritic arbors, dendritic spine "dysgenesis" and excitation inhibition imbalance are main traits assumed to underlie impaired cognition and behavioral adaptation in intellectual disability. However, how these modifications actually contribute to functional properties of neuronal networks, such as signal integration or storage capacity is unknown. Here, we used a mouse model overexpressing Dyrk1A (Dual-specificity tyrosine [Y]-regulated kinase), one of the most relevant Down syndrome (DS) candidate genes, to gather quantitative data regarding hippocampal neuronal deficits produced by the overexpression of Dyrk1A in mice (TgDyrk1A; TG). TG mice showed impaired hippocampal recognition memory, altered excitation-inhibition balance and deficits in hippocampal CA1 LTP. We also detected for the first time that deficits in dendritic arborization in TG CA1 pyramidal neurons are layer-specific, with a reduction in the width of the stratum radiatum, the postsynaptic target site of CA3 excitatory neurons, but not in the stratum lacunosum-moleculare, which receives temporo-ammonic projections. To interrogate about the functional impact of layer-specific TG dendritic deficits we developed tailored computational multicompartmental models. Computational modelling revealed that neuronal microarchitecture alterations in TG mice lead to deficits in storage capacity, altered the integration of inputs from entorhinal cortex and hippocampal CA3 region onto CA1 pyramidal cells, important for coding place and temporal context and on connectivity and activity dynamics, with impaired the ability to reach high {gamma} oscillations. Contrary to what is assumed in the field, the reduced network activity in TG is mainly contributed by the deficits in neuronal architecture and to a lesser extent by over-inhibition. Finally, given that therapies aimed at improving cognition have also been tested for their capability to recover dendritic spine deficits and excitation-inhibition imbalance, we also tested the short- and long-term changes produced by exposure to environmental enrichment (EE). Exposure to EE normalized the excitation inhibition imbalance and LTP, and had beneficial effects on short-term recognition memory. Importantly, it produced massive but transient dendritic remodeling of hippocampal CA1, that led to recovery of high {gamma} oscillations, the main readout of synchronization of CA1 neurons, in our simulations. However, those effects where not stable and were lost after EE discontinuation. We conclude that layer-specific neuromorphological disturbances produced by Dyrk1A overexpression impair coding place and temporal context. Our results also suggest that treatments targeting structural plasticity, such as EE, even though hold promise towards improved treatment of intellectual disabilities, only produce temporary recovery, due to transient dendritic remodeling.

neuroscience↗

bioRxiv2023

A novel regulatory mechanism of actin cytoskeleton dynamics through a neural microexon in DAAM1 is necessary for memory formation

Actin cytoskeleton dynamics is critical for nervous system development and function, yet the role of alternative splicing in controlling these processes is poorly understood. A highly conserved subset of neuronal-specific microexons coordinates fundamental aspects of nervous system biology. A subset of these exons is enriched in genes involved in actin cytoskeleton, yet their functions are unknown. Here, we focus on a microexon in DAAM1, a member of the formin-homology-2 (FH2) domain class of proteins, which have diverse functions associated with the reorganization of the actin cytoskeleton. Remarkably, splicing of the microexon extends the linker region of the DAAM1 FH2 domain and leads to qualitative and quantitative changes in actin polymerization. Deletion of the microexon results in neuritogenesis defects and increased calcium influx in differentiated neurons. Moreover, mice harboring the deletion exhibit postsynaptic defects, reduced number of immature dendritic spines, impaired long-term potentiation, and deficits in memory formation. These deficits are associated with increased RHOA/ROCK signaling, pivotal in controlling actin-cytoskeleton dynamics, and were rescued by treatment with a ROCK inhibitor. We thus demonstrate that a conserved neuronal microexon in DAAM1 is critical for controlling actin dynamics through the RHOA/ROCK signaling pathway and is necessary for normal cognitive functioning.

neuroscience↗

bioRxiv2023

Defective engram allocation contributes to impaired fear memory performance in Down syndrome

Down syndrome (DS) is the most common genetic form of intellectual disability (ID). The cellular and molecular mechanisms contributing to ID in DS are not completely understood. Recent evidence indicates that a given memory is encoded by sparsely distributed neurons, highly activated during learning, the engram cells. Intriguingly, mechanisms that are of paramount importance for engram formation are impaired in DS. Here we explored engram formation in a DS mouse model, the Ts65Dn and we found a reduced number of engram cells in the dentate gyrus (DG), suggesting reduced neuronal allocation to engrams. We also show that trisomic engram cells present reduced number of mature spines than WT engram cells and their excitability is not enhanced during memory recall. In fact, activation of engram cells using a chemogenetic approach does not recover memory deficits in Ts65Dn. Altogether, our findings suggest that perturbations in engram neurons may play a significant role in memory alterations in DS.

neuroscience↗

bioRxiv2021

A new analytical pipeline reveals metatranscriptomic changes upon high-fat diet in a Down syndrome mouse model.

The existing methods designated for metatranscriptomic studies are still rare and being developed. In this paper we present a new analytical pipeline combining contig assembly, gene selection and functional annotation. This pipeline allowed us to reconstruct contigs with very high unique mappability (83%) and select sequences encoding putative bacterial genes reaching also a very high (66%), unique mappability of the NGS sequencing reads. Then, we have applied our pipeline to study faecal metatranscriptome of a Down syndrome (DS) mouse model, the Ts65Dn mice, in order to identify the differentially expressed transcripts. Recent studies have implicated dysbiosis of gut microbiota in several central nervous system (CNS) disorders, including DS. Given that DS individuals have an increased prevalence of obesity, we also studied the effects of a high-fat diet (HFD) on the transcriptomic changes of mice gut microbiomes, as the complex symbiotic relationship between the gut microbiome and its host is strongly influenced by diet and nutrition. Using our new pipeline we found that compared to wild type (WT), Ts65Dn mice showed an elevated expression levels of genes involved in hypoxanthine metabolism, which contributes to oxidative stress, and a down-regulated expression of genes involved in interactions with host epithelial cells and virulence. Microbiomes of mice fed HFD showed significantly higher expression levels of genes involved in membrane lipopolysaccharides / lipids biosynthesis, and decreased expression of osmoprotection and lysine fermentation genes, among others. We also found evidence that mice microbiota is capable of expressing genes encoding for neuromodulators, which may play a role in development of compulsive overeating and obesity. Our results show a DS-specific metatranscriptome profile and show that a high-fat diet affects the metabolism of mice gut microbiome by changing activity of genes involved in lipids, sugars, proteins and amino acids metabolism and cell membranes turnover. Our new analytical pipeline combining contig assembly, gene selection and functional annotation provides new insights into the metatranscriptomic studies.

bioinformatics↗

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↗

bioRxiv2021

The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians

The eutherian placenta is a major site for parental genetic conflict. Here, we identify the X-linked Mbnl3 gene as a novel player in this dispute. Mbnl3 belongs to an RNA binding protein family whose members regulate alternative splicing and other aspects of RNA metabolism in association with cellular differentiation. We find that, in eutherians, Mbnl3 has become specifically expressed in placenta and has undergone accelerated sequence evolution leading to changes in its RNA binding specificities. Although its molecular roles are partly redundant with those of Mbnl2, Mbnl3 has also acquired novel biological functions. In particular, whereas Mbnl2;Mbnl3 double knockout mice display severe placental maturation defects leading to strong histological and functional abnormalities, Mbnl3 knockout alone results in increased placental growth and favors placental and fetal resource allocation during limiting conditions.

evolutionary biology↗

bioRxiv2021

A deep learning approach to neurite prediction in high throughput fluorescence imaging

Changes to neuronal morphology and loss of neurites and synaptic connections can be an important early indicator of neurological diseases, and a pathognomonic sign of neurodevelopmental disorders. These changes are typically detectable by microscopy in cell culture or histological samples, but quantification can be challenging. The neurites extending from cell soma can be quite thin, dim, overlapping and complex, making them laborious to trace manually and difficult to annotate and quantify computationally or automatically. Moreover, the tools available to aid this aim are limited in their capacity to generalize to high throughput image acquisition such as time-lapse or longitudinal imaging, where imaging conditions can change dramatically over the course of the experiment. In order to facilitate neurite quantification, we developed a deep learning (DL) neurite annotation prediction algorithm (NAPA) to predict the structure and length of neurites. NAPA overcomes experimental variation inherent to fluorescence imaging by learning more broader features that are important for neurite recognition. Based on a dataset with partial annotation, NAPA generated predictions on several unannotated datasets, and was able to capture differences between disease and control conditions. We also defined a sequence of steps to generate custom models with a small number of annotation inputs, and extended the predictions to a 3D tissue sample and longitudinal imaging. With this algorithm we developed an approach to quantify neurites with an accuracy that nears and sometimes exceeds human curation, in 1/100th of the time. This approach makes accurate analysis of large or longitudinal datasets feasible across a broad range of datasets.

neuroscience↗

bioRxiv2021

Environmental enrichment induces epigenomic and genome organization changes relevant for cognitive function

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization. Highlights- Environmental enrichment (EE) alters chromatin conformation, CTCF binding, and spatially 3D genome changes, thereby regulating cognitive function during the first steps of life after birth. - Transcription-associated gene body marks H3K79me2 and H3K36me3 are differently influenced by EE in cortical brain cells and binding is exacerbated upon stimulation in an age-dependent manner. - EE-induced changes of 3D genome organization increase inter-chromosomal interactions of genes associated with synaptic transmission and AMPA receptor genes on chromosomes 7 and 17.

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↗

bioRxiv2018

Epigallocatechin-3-Gallate Improves Facial Dysmorphology Associated with Down Syndrome

In Down syndrome (DS), the overall genetic imbalance caused by trisomy of chromosome 21 leads to a complex pleiotropic phenotype that involves a recognizable set of facial traits. Several studies have shown the potential of epigallocatechin-3-gallate (EGCG), a green tea flavanol, as a therapeutic tool for alleviating different developmental alterations associated with DS, such as cognitive impairment, skull dysmorphologies, and skeletal deficiencies. Here we provide for the first time experimental and clinical evidence of the potential benefits of EGCG treatment to facial morphology. Our results showed that mouse models treated with low dose of EGCG during pre- and postnatal development improved facial dysmorphology. However, the same treatment at high dose produced disparate facial morphology changes with an extremely wide and abnormal range of variation. Our observational study in humans revealed that EGCG treatment since early in development is associated with intermediate facial phenotypes and significant facial improvement scores. Overall, our findings suggest a potential beneficial effect of ECGC on facial development, which requires further research to pinpoint the optimal dosages of EGCG that reliably improve DS phenotypes. Current evidence warns against the non-prescribed intake of this supplement as a health-promoting measure.

pathology↗