Biology subjects

Chevalier, C.

Publications and source records attributed to Chevalier, C..

At least 19 recordsLinked to original sources

bioRxiv2026

LONG-TERM NEURODEVELOPMENTAL AND COGNITIVE OUTCOMES FOLLOWING PRENATAL INHIBITION OF DYRK1A BY LEUCETTINE L41 IN MOUSE MODELS OF DOWN SYNDROME

Down syndrome (DS), caused by trisomy of human chromosome 21, is characterized by intellectual disability and cognitive deficits, partly driven by the overexpression of Dual-specificity tyrosine-(Y)-phosphorylation Regulated Kinase 1A (DYRK1A). While postnatal DYRK1A inhibition has shown promise in improving cognition in DS models, its therapeutic potential during embryonic development, a critical window for neurogenesis, remains unexplored. Here, we tested the hypothesis that prenatal inhibition of DYRK1A could mitigate long-term cognitive impairments in DS. We administered Leucettine L41, a potent and selective DYRK1A inhibitor, to pregnant dams carrying two DS mouse models: Ts65Dn and Dp(16)1Yey, both of which recapitulate trisomy of genes homologous to human chromosome 21, including Dyrk1a. Treatment was designed to suppress DYRK1A kinase activity during embryogenesis. In adulthood, we evaluated the progeny for cognitive performance, gene expression profiles linked to DS phenotypes, and neuronal maturation markers. Prenatal L41 treatment produced lasting effects in both models, rescuing specific behavioral deficits and modulating the expression of DS-implicated genes, including the excitatory/inhibitory balance regulator GAD67. However, model-specific responses were observed: hyperactivity, working memory deficits, and GAD67-positive cell counts remained uncorrected in Ts65Dn mice, suggesting divergent molecular pathways underlying shared DS phenotypes. This study demonstrates the therapeutic potential of prenatal DYRK1A inhibition for DS and provides novel insights into its role in neurodevelopmental trajectories and cognitive outcomes. Our findings underscore the importance of timing and genetic context in DS intervention strategies.

neuroscience↗

bioRxiv2026

Differential efficacy of α5IA in the Dp(16)1Yey mouse model of Down syndrome: implications for translational research

Cognitive impairments significantly impact the daily life of people with Down syndrome (DS). Overinhibition mediated by interneurons in the central nervous system was proposed as a key pathophysiological mechanism. Previous studies demonstrated cognitive rescue in the Ts65Dn mouse model using 5IA, a negative allosteric modulator of the 5 subunit-containing GABAA receptors. Here, we evaluated the effect of this drug in a mouse model carrying a more accurate duplication of the orthologous region to the human chromosome 21, namely the Dp(16)1Yey mouse model. First, we expanded the phenotypic characterization of Dp(16)1Yey mice using translationally more relevant behavioral tests. We confirmed spatial memory deficits in Dp(16)1Yey mice in the Barnes maze, and highlighted robust learning deficits in the pattern dissociation task and impairments in motor coordination. Next, we evaluated the effect of 5IA treatment on cognitive and motor performance. While 5IA treatment improved motor coordination in the Dp(16)1Yey mice, it failed to restore cognitive performance in the Barnes maze or in the pattern dissociation task. These findings could suggest divergent pathophysiological mechanisms between the Dp(16)1Yey and the Ts65Dn models. Potentially, it could explain the limited efficacy of similar pharmacological intervention in clinical trials for DS. Further preclinical studies should prioritize refined behavioral paradigms and probably the use of more complex DS models to enhance the translational potential of candidate therapies.

neuroscience↗

bioRxiv2026

Pneumococcus drives STAT3 activation of lower airway epithelium in a strain and burden-dependent manner

Crosstalk between respiratory bacteria and human airway epithelial cells initiates cellular immunity, yet the molecular determinants of asymptomatic carriage versus inflammation remain incompletely understood. A key regulator of airway epithelial cellular immunity is the Signal Transducer and Activator of Transcription (STAT3). Once activated by phosphorylation this host transcription factor signals through two cascades, canonical by phosphorylation at tyrosine 705 and non-canonical by phosphorylation at serine 727, which contributes to bacterial clearance and immune defense in pneumonia. Despite this, its role in epithelial responses to Streptococcus pneumoniae has not been defined. Revealing these processes are particularly important for understanding the variability in pathogenic potential for the pathobiont Streptococcus pneumoniae which triggers either host commensal-like carriage or susceptibility at this interface. Here we investigated the role of STAT3 signaling during pneumococcal challenge using lower airway epithelial cells and two pneumococcal isolates favoring either commensal-like carriage, 6B ST90, or with pathogenic potential, TIGR4. We show the invasive TIGR4 strain drives canonical STAT3 phosphorylation and suppresses non-canonical STAT3 in a burden-dependent manner. This contrasts with the 6B ST90 isolate which requires a 20-fold increase in burden to elicit minimal STAT3 responses. TIGR4 activation correlated with SOCS3 expression, while knockdown of endogenous STAT3 did not alter pneumococcal adherence or epithelial membrane integrity. Mechanistically, STAT3 activation required live bacteria and pneumolysin production but was independent of bacterial hydrogen peroxide. Altogether we reveal previously unrecognized divergence in STAT3 signaling during pneumococcal infection.

microbiology↗

bioRxiv2025

MultiSpecies Canopy Segmentation: Interactive Machine-Learning and Pseudo-Labelling are key

This study investigates the challenge of creating datasets for training multiclass deep-learning segmentation models, specifically for segmenting multi-species canopy images. Creating training sets for deep-learning based segmentation of multispecies canopies is currently too labor-intensive and time-consuming to be viable. To address this challenge, we propose a novel pipeline that uses fully convolutional neural networks (FCNNs) to transition from single-species images to segmented multi-species images. This paper demonstrates that FCNNs can effectively generalize learning from single-species canopy images to multispecies canopy images, achieving accurate pixel classification in mixed species canopies even when the network was trained only on images of single-species canopies. Additionally, we introduce Interactive Machine Learning and pseudo labeling as a method for generating a single-species canopy training set in a matter of minutes. We also present two software packages to implement our approach and extensively evaluate them against several baselines. Our findings demonstrate that our approach can significantly reduce the human time load required for semantic segmentation of multispecies canopy images, achieving over 90% accuracy in less than 10 minutes. This new method has the potential to greatly facilitate the study of multispecies canopies.

bioengineering↗

bioRxiv2025

Clonal analysis of SepSecS-specific CD4 T cells reveals a new HLA-DPA102:01/HLA-DPB101:01-restricted immunodominant epitope in autoimmune hepatitis

Autoreactive CD4 T cells, recognizing liver-self-antigens such as SepSecS, are main drivers of the chronic inflammatory response during autoimmune hepatitis (AIH). Previous studies have uncovered immunodominant SepSecS epitopes often associated with HLA-DRB1*03 or HLA-DRB1*04 restriction, two alleles enriched in AIH population. However, HLA restriction of numerous SepSecS epitopes remains incomplete and it is still unclear if immunodominant epitopes could be presented by non-HLA-DR molecules. Here, we investigated epitope recognition of SepSecS-specific TCRs isolated from AIH patients, and their HLA restriction by generating TCR hybridoma cell lines. Seventeen TCRs recognized eight SepSecS epitopes with four distinct HLA restrictions, including a novel HLA-DPA1*02:01/DPB1*01:01-restricted SepSecS epitope. TCR clustering analysis using GLIPH2 algorithm suggested that this epitope is recognized by multiple distinct TCRs in HLA-DPA1*02:01[~]HLA-DPB1*01:01 patients. Our study provides new insights into liver-self-antigen T cell reactivity during AIH, which could offer potential therapeutic strategies by targeting autoreactive CD4 T cells.

immunology↗

bioRxiv2025

Accumulation of PD-1+ TIGIT+ T cells in the liver after local antigen reactivity and during autoimmune hepatitis

In autoimmune hepatitis (AIH), hepatocellular damage is linked to an accumulation of autoreactive T cells in the liver of patients, but how these cells emerge in the tissue remains unclear. Here we used a mouse model based on recombination-dependent inducible expression of influenza A hemagglutinin (HA) by hepatocytes to investigate initiation of liver antigen-specific response. Our study revealed that peripheral immunization, unlike inflammatory triggers, is essential to initiate an immune response against a liver antigen. We showed that liver T cell reactivity after peripheral immunization is marked by PD-1 and TIGIT co-expression and that the frequency of PD-1+ TIGIT+ HLA-DR+ CD38+ CD8 T cells in the blood of AIH patients is associated with liver injury. Our findings suggest a potential influence of the peripheral immunization for the liver-antigen-specific responses during AIH. Liver tissue-activated T cells probably recirculate during active phase of the disease, unveiling potential immunomarkers to monitor disease activity. HighlightsO_LIPeripheral immunization rather than local inflammation induces an immune response against a hepatic antigen C_LIO_LIPD-1 and TIGIT co-expression by T cells is found after tissue antigen-specific T cell reactivity C_LIO_LIFrequency of circulating PD-1+ TIGIT+ HLA-DR+ CD38+ CD8 T cells is associated with AIH disease activity C_LI In briefGuinebretiere et al. demonstrate that after peripheral immunization, liver-antigen-specific T cell accumulation in the tissue is marked by local PD-1/TIGIT co-expression, a phenotype shared with liver and circulating T cell subsets enriched in active autoimmune hepatitis (AIH) patients. These findings suggest the influence of peripheral immunization on the initiation of AIH and provide potential immunomarker of AIH activity.

immunology↗

bioRxiv2025

Functional analysis of FW2.2-LIKE proteins in tomato: SlFWL5 regulates leaf size and morphology.

The CELL NUMBER REGULATOR/FW2.2-like (CNR/FWL) gene family comprises PLAC8 domain-containing membrane-associated proteins. The CNR/FWL gene family was named in reference to its founding member, the FW2.2 gene, which determines fruit size in tomato via a negative regulation on cell divisions. The functional characterization of PLAC8 domain-containing CNR/FWL proteins in plants is still very scarce, and only recently the molecular and cellular mode of action of FW2.2 was identified as regulating plasmodesmata-mediated cell-to-cell communication. In the present study, we provided a functional analysis of SlFWL genes in tomato, aiming at investigating any direct role in the control of organ growth. Based on a combination of molecular and cellular approaches, we selected three SlFWL proteins, namely SlFWL2, -4 and -5, which are localized at the plasma membrane. Gain- and loss-of-function transgenic plants were generated to explore their putative role as regulators of organ growth in tomato. This allowed us to shed light more specifically on the critical involvement of SlFWL5 in leaf development. We here showed that SlFWL5 is a plasmodesmata-localized protein that regulates leaf size and morphology via cell expansion, most probably through cell-to-cell communication. This original finding underscores further the importance of the CNR/FWL family members in growth regulation. Highlight: The FW2.2-LIKE protein SlFWL5 is localized at plasmodesmata and may have a role in cell-to-cell communication to regulate cell expansion during leaf development.

plant biology↗

bioRxiv2024

A floor-field model of tau-taxol competition explains tau envelope dynamics on taxol-stabilized microtubules

Tau is a microtubule-associated protein (MAP) that is highly expressed in neurons. Recent in-vitro studies have shown that tau molecules can segregate into cohesive envelopes on paclitaxel (taxol) stabilized microtubules. These envelopes act as selective barriers gating the motor transport and protecting microtubules against the action of severing enzymes. However, the mechanisms underlying the formation of these envelopes remain unclear. Recent in vitro reconstitution assays revealed that the formation of tau envelopes induces a compaction of the underlying microtubule lattice, whereas taxol binding induces lattice expansion, indicating competitive binding between tau and taxol on microtubules. In this study, we use physical modeling to investigate how this competition between tau and taxol regulates the formation of tau envelopes. Our model includes static and dynamic floor-fields, concepts adapted from pedestrian dynamics. By comparing our simulation results with experimental data, we demonstrate that tau-taxol competition on the microtubule lattice is sufficient to explain the features of the formation and disassembly of tau envelopes. Notably, tau-tau interactions are not necessary to account for the steadiness of these envelopes.

biophysics↗

bioRxiv2024

Ripply3 overdosage induces mid-face shortening through Tbx1 downregulation in Down syndrome models.

The most frequent and unique features of Down syndrome (DS) are learning disability and ucraniofacial (CF) dysmorphism. The DS-specific CF features are an overall reduction in head dimensions (microcephaly), relatively wide neurocranium (brachycephaly), reduced mediolaterally orbital region, reduced bizygomatic breadth, small maxilla, small mandible, and increased individual variability. Until now, the cellular and molecular mechanisms underlying the specific craniofacial phenotype have remained poorly understood. Investigating a new panel of DS mouse models with different segmental duplications on mouse chromosome 16 in the region homologous to human chromosome 21, we identified new regions and the role of two candidate gene for DS-specific CF phenotypes. First, we confirmed the role of Dyrk1a in the neurocranium brachycephaly. Then, we identified the role of the transcription factor Ripply3 overdosage in midface shortening through the downregulation of Tbx1, another transcription factor involved in the CF midface phenotype encountered in DiGeorge syndrome. This last effect occurs during branchial arches development through a reduction in cell proliferation. Our findings define a new dosage-sensitive gene responsible for the DS craniofacial features and propose new models for rescuing all aspects of DS CF phenotypes. This data may also provide insights into specific brain and cardiovascular phenotypes observed in DiGeorge and DS models, opening avenues for potential targeted treatment to soften craniofacial dysmorphism in Down syndrome.

genetics↗

bioRxiv2024

Transcriptomic, clonal, and functional analyses reveal Liver tissue-imprinted immuno-profile of circulating autoreactive CD4 T cells in autoimmune liver diseases

Autoimmune liver diseases (AILD) are immune-mediated disorders in which CD4 T cells play a central role. However, the link between circulating self-antigen-specific CD4 T cells and the targeted tissue has not been extensively studied in AILD. We hypothesized that circulating autoreactive CD4 T cells were clonally and functionally related to dominant intra-hepatic pathogenic CD4 T cell clones. Single cell transcriptomic analysis of circulating self-antigen-specific CD4 T cells revealed a specific B-helper and immuno-exhausted transcriptional profile, which was conserved for different autoantigens, but distinct from several other types of foreign antigen specificities. In the blood, the dominant hepatic CD4 T cell clones had a similar transcriptomic signature and were enriched in the PD-1+ TIGIT+ HLA-DR+ CD4 T cell subset. In a mouse model, antigen-specific CD4 T cells acquired the immuno-exhausted transcriptional profile when they accumulated in the liver after local antigen reactivity. Locally, immune checkpoint molecules controlled the response of antigen-specific CD4 T cells responsible for liver damage. Our study reveals the origin and biology of liver-derived autoreactive CD4 T cells in the blood of AILD patients that are imprinted by the liver environment, and suggest a dysregulation of the immune checkpoint molecules pathways. Our study enables tracking and isolating circulating autoreactive CD4 T cells for future diagnostic and therapeutic purposes.

immunology↗

bioRxiv2023

The FW2.2/CNR protein regulates cell-to-cell communication in tomato by modulating callose deposition at plasmodesmata

The FW2.2 gene is the founding member of the CELL NUMBER REGULATOR (CNR) gene family. More than 20 years ago, FW2.2 was the first cloned gene underlying a Quantitative Trait Locus (QTL) governing fruit size/weight in tomato. However, despite this discovery, the molecular mechanisms by which FW2.2 acts as a negative regulator of cell divisions during fruit growth remain undeciphered. In the present study, we confirm that FW2.2 is a transmembrane spanning protein, whose both N- and C-terminal ends are facing the apoplast. We unexpectedly found that FW2.2 is located at plasmodesmata (PD). FW2.2 participates in the spatiotemporal regulation of callose deposition at PD via an interaction with Callose Synthases, which suggests a regulatory role in cell-to-cell communication by modulating PD transport capacity and trafficking of signaling molecules during fruit development.

plant biology↗

bioRxiv2023

Ploidy-specific transcriptomes shed light on the heterogeneous identity and metabolism of developing pericarp cells

Endoreduplication, during which cells increase their DNA content through successive rounds of full genome replication without cell division, is the major source of endopolyploidy in higher plants. Endoreduplication plays pivotal roles in plant growth and development and is associated with the activation of specific transcriptional programs that are characteristic to each cell type, thereby defining their identity. In plants, endoreduplication is found in numerous organs and cell types and especially in agronomically valuable ones, such as the fleshy fruit (pericarp) of tomato presenting high ploidy levels. We used the tomato pericarp tissue as a model system to explore the transcriptomes associated with endoreduplication progression during fruit growth. We confirmed that expression globally scales with ploidy level and identified sets of genes differentially expressed when comparing ploidy levels at a specific developmental stage. We found that non-endoreduplicated cells are defined by cell division state and cuticle synthesis while endoreduplicated cells are mainly defined by their metabolic activity changing rapidly over time. By combining this dataset with publicly available spatiotemporal pericarp expression data, we proposed a map describing the distribution of ploidy levels within the pericarp. These transcriptome-based predictions were validated by quantifying ploidy levels within the pericarp tissue. This in situ ploidy quantification revealed the dynamic progression of endoreduplication and its cell layer specificity during early fruit development. In summary, the study sheds light on the complex relationship between endoreduplication, cell differentiation, and gene expression patterns in the tomato pericarp. Significance statementThe progression of endoreduplication is very dynamic during early fruit development and displays cell layer specific patterns. The integration of ploidy distribution maps with ploidy-specific transcriptome data revealed that gene expression in the pericarp is controlled in a ploidy-specific manner during the early stages of tomato fruit development, resulting in the spatialization of transcriptional programs.

plant biology↗

bioRxiv2023

Epithelial cells maintain memory of prior infection with Streptococcus pneumoniae through di-methylation of histone H3

Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumonia. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. In this study, we demonstrate that S. pneumoniae actively induces di-methylation of lysine 4 on histone H3 (H3K4me2), which persists for at least 9 days upon clearance of bacteria with antibiotics. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses for subsequent infection.

cell biology↗

bioRxiv2023

Cardiopharyngeal Mesoderm specification into cardiac and skeletal muscle lineages in gastruloids.

Cardiopharyngeal mesoderm contributes to the formation of the heart and head muscles. However, the mechanisms governing cardiopharyngeal mesoderm specification remain unclear. Indeed, there is a lack of an in vitro model replicating the differentiation of both heart and head muscles to study these mechanisms. Such models are required to allow live-imaging and high throughput genetic and drug screening. Here, we show that the formation of self-organizing or pseudo-embryos from mouse embryonic stem cells (mESCs), also called gastruloids, reproduces cardiopharyngeal mesoderm specification towards cardiac and skeletal muscle lineages. By conducting a comprehensive temporal analysis of cardiopharyngeal mesoderm establishment and differentiation in gastruloids and comparing it to mouse embryos, we present the first evidence for skeletal myogenesis in gastruloids. By inferring lineage trajectories from the gastruloids single-cell transcriptomic data, we further suggest that heart and head muscles formed in gastruloids derive from cardiopharyngeal mesoderm progenitors. We identify different subpopulations of cardiomyocytes and skeletal muscles, which most likely correspond to different states of myogenesis with "head-like" and "trunk-like" skeletal myoblasts. These findings unveil the potential of mESC-derived gastruloids to undergo specification into both cardiac and skeletal muscle lineages, allowing the investigation of the mechanisms of cardiopharyngeal mesoderm differentiation in development and how this could be affected in congenital diseases.

developmental biology↗

bioRxiv2023

Influence of oceanography and geographic distance on genetic structure: how varying the sampled domain influences conclusions in Laminaria digitata

Understanding the environmental processes shaping connectivity can greatly improve management and conservation actions which are essential in the trailing edge of species distributions. In this study, we used a dataset built from 32 populations situated in the southern limit of the kelp species Laminaria digitata. By extracting data from 11 microsatellite markers, our aim was to (1) refine the analyses of population structure, (2) compare connectivity patterns and genetic diversity between island and mainland populations and (3) evaluate the influence of sampling year, hydrodynamic processes, habitat discontinuity, spatial distance and sea surface temperature on the genetic structure using a distance-based redundancy analysis (db-RDA). Analyses of population structure enabled to identify well connected populations associated to high genetic diversity, and others which appeared genetically isolated from neighboring populations and showing signs of genetic erosion verifying contrasting ecological (and demographic) status in Brittany and the English Channel. By performing db-RDA analyses on various sampling sizes, geographic distance appeared as the dominant factor influencing connectivity between populations separated by great distances, while hydrodynamic processes were the main factor at smaller scale. Finally, Lagrangian simulations enabled to study the directionality of gene flow which has implications on source-sink dynamics. Overall, our results have important significance in regard to the management of kelp populations facing pressures both from global warming and their exploitation for commercial use.

evolutionary biology↗

bioRxiv2023

NetSyn: genomic context exploration of protein families

Background: The growing availability of large prokaryotic genomic datasets presents an opportunity to discover new metabolic pathways and enzymatic reactions useful for industrial or synthetic biological applications. Efforts to identify new enzyme functions in this vast number of sequences cannot be achieved without bioinformatics tools and the development of new strategies. Standard methods for assigning a biological function to a gene are based on sequence similarity. However, complementary approaches rely on mine databases to identify conserved gene clusters (i.e. syntenies). In prokaryotic genomes, genes involved in the same pathway are frequently encoded in a single locus with an operonic organisation. This genomic context conservation is considered as a reliable indicator of functional relationships, and is therefore a promising approach for improving the gene function prediction. Methods. Here we present NetSyn (Network Synteny), a tool to group protein sequences based on the conservation of their genomic context rather than solely on sequence similarity. From a list of protein sequence identifiers, NetSyn searches corresponding genome entries to retrieve neighboring genes. Corresponding protein sequences are grouped into families to define homology relationships and compute a synteny conservation score between the different extracted genomic contexts. A network is then created in which the nodes represent the input proteins and the edges indicate that two proteins share a conserved synteny. Finally, the network is partitioned into clusters grouping proteins with similar genomic contexts, using a community detection algorithm. Results. As a proof of concept, we used NetSyn on two different datasets. The first one is the BKACE protein family (formerly named DUF849) which has previously been divided into isofunctional sub-families. NetSyn was able to go a step further by providing additional sub-families beyond those already described. The second dataset corresponds to a set of non-homologous proteins belonging to three different glycoside hydrolase (GH) families. These GHs are known to work cooperatively in a Polysaccharide-Utilization Loci (PUL) and are therefore grouped together in the same genomic contexts. NetSyn was able to identify a locus grouping 3 GHs, involved in the degradation of xyloglucan, in 162 prokaryotic genomes. Discussion. By highlighting conserved synteny in distantly related prokaryotic species, NetSyn enables functional links between proteins to be established beyond sequence similarity alone. We showed that NetSyn is efficient for exploring large prokaryotic protein families, enabling the definition of isofunctional groups and the identification of functional interactions between non-homologous enzymes. These features enable the prediction of new genomic structures that have not yet been experimentally characterized. Finally, NetSyn is also useful for pinpointing annotation errors that have been propagated across databases, and for suggesting annotations on proteins lacking functional prediction. NetSyn is freely available at https://github.com/labgem/netsyn.

bioinformatics↗

bioRxiv2023

Streptococcus pneumoniae drives specific and lasting Natural Killer cell memory

NK cells are important mediators of innate immunity and play an essential role for host protection against infection, although their responses to bacteria are poorly understood. Recently NK cells were shown to display memory properties, as characterized by an epigenetic signature leading to a stronger secondary response. Although NK cell memory could be a promising mechanism to fight against infection, it has not been described upon bacterial infection. Here, we reveal that NK cells develop specific and long-term memory following sub-lethal infection with the extracellular pathogen Streptococcus pneumoniae. Memory NK cells display intrinsic sensing and response to bacteria in vitro, in a manner that is enhanced post-bacterial infection. In addition, their transfer into naive mice confer protection from lethal infection for at least 12 weeks. Interestingly, NK cells display enhanced cytotoxic molecule production upon secondary stimulation and their protective role is dependent on Perforin and independent of IFN{gamma}. Thus, our study identifies a new role for NK cells during bacterial infection, opening the possibility to harness innate immune memory for therapeutic purposes.

microbiology↗

bioRxiv2022

A 16p11.2 deletion mouse model displays quantitatively and qualitatively different behaviours in sociability and social novelty over short- and long-term observation.

BackgroundAutism spectrum disorders affect more than one percent of the population, impairing social communication and increasing stereotyped behaviours. A micro-deletion of the 16p11.2 BP4-BP5 chromosomic region has been identified in one percent of patients also displaying intellectual disabilities. In mouse models generated to understand the mechanisms of this deletion, learning and memory deficits were pervasive in most genetic backgrounds, while social communication deficits were only detected in some models. MethodsBased on previous study (Arbogast et al. 2016 PLoS genetics), we itemized the social deficits in the mouse model of 16p11.2 deletion on a hybrid C57BL/6NxC3H.Pde6b+ genetic background. We examined whether behavioural deficits were visible over long-term observation periods, to parallel everyday-life assessment of patients. We recorded the individual and social behaviours of 16p11.2 Del/+ mice and their wild-type littermates from both sexes in long-term (over two and three consecutive nights) social interactions of familiar mixed-genotype quartets of males and of females, and of same-genotype unfamiliar female pairs. ResultsWe observed that Del/+ mice of both sexes increased significantly their locomotor activity compared to wild-type littermates over long-term monitoring. In the social domain, Del/+ mice of both sexes displayed widespread deficits over long-term monitoring, even more so in males than in females in quartets of familiar individuals. In pairs, significant perturbations of the organisation of the social communication and behaviours appeared in Del/+ females. DiscussionAltogether, this suggests that, over long recording periods, the phenotype of the 16p11.2 Del/+ mice was differently affected in the locomotor activity and the social domains and between the two sexes. These findings confirm the importance of testing models in long-term conditions to provide a comprehensive view of their phenotype that will refine the study of cellular and molecular mechanisms and complement pre-clinical targeted therapeutic trials.

animal behavior and cognition↗