Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders

Lorenzo, Sandra Martín; Moreno, Maria del Mar Muñiz; Atas, Helin; Pellen, Marion; Nalesso, Valérie; Raffelsberger, Wolfgang; Prevost, Geraldine; Lindner, Loïc; Birling, Marie‐Christine; Ménoret, Séverine; Tesson, Laurent; Négroni, Luc; Concordet, Jean-Paul; Anegón, Ignacio; Hérault, Yann

doi:10.1101/2023.02.11.528123

Cited by 3 publications

(4 citation statements)

References 52 publications

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“…Similarly, in the social domain, the contribution of each gene within the deleted region could also be detailed, as it has been done to identify the contribution of Kctd13 gene to the cognitive impairment phenotype (Arbogast et al, 2019;Martin Lorenzo et al, 2021). To ascertain the robustness of these findings, a cross-species comparison should be conducted in the rat model (Martin Lorenzo et al, 2023), as recommended in recent guidelines to increase the value and robustness of preclinical models (Silverman et al, 2022). Rescue strategies could then be attempted, with for instance R-baclofen, a GABAb agonist, or Fasudil, an inhibitor of the Rho-associated protein kinase, both restoring the cognitive deficits in the mouse model (Stoppel et al, 2018;Martin Lorenzo et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Day-to-day spontaneous social behaviours is quantitatively and qualitatively affected in a 16p11.2 deletion mouse model

Rusu,

Chevalier,

de Chaumont

et al. 2023

Front. Behav. Neurosci.

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BackgroundAutism spectrum disorders affect more than 1% 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 1% 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.MethodsTo complement previous studies, we itemized the social deficits in the mouse model of 16p11.2 deletion on a hybrid C57BL/6N × C3H.Pde6b+ genetic background. We examined whether behavioural deficits were visible over long-term observation periods lasting several days and nights, to parallel everyday-life assessment of patients. We recorded the individual and social behaviours of mice carrying a heterozygous deletion of the homologous 16p11.2 chromosomic region (hereafter Del/+) and their wild-type littermates from both sexes over two or three consecutive nights during 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. In the social domain, Del/+ mice of both sexes displayed widespread deficits, 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.

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Section: Discussionmentioning

confidence: 99%

Day-to-day spontaneous social behaviours is quantitatively and qualitatively affected in a 16p11.2 deletion mouse model

Rusu,

Chevalier,

de Chaumont

et al. 2023

Front. Behav. Neurosci.

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“…Rat models for 16p11.2 CNVs have also been generated recapitulating craniofacial phenotypes, with mirror effects between the DEL and the DUP conditions (Qiu et al, 2019). Converging and male-specific deficits in social behaviour and novel object recognition have been also observed in 16p11.2 DEL and DUP rats in two different genetic backgrounds (Martin Lorenzo et al, 2023). RNA sequencing analysis in the hippocampus found 267 differentially expressed genes dysregulated in DEL and DUP rat models.…”

Section: Other Animal Models 16p112 Del and Dup Rat Modelsmentioning

confidence: 92%

“…Frontiers in Pharmacology frontiersin.org 13 Differential functional analysis revealed 23 upregulated pathways in both DEL and DUP rats, associated with morphogenesis of the primary cilium. However, pathways related to synaptic function and metabolism were mostly deregulated in DEL rats, while pathways associated with transcription, epigenomic regulation and hormone regulation were mostly affected in DUP animals (Martin Lorenzo et al, 2023).…”

Section: Other Animal Models 16p112 Del and Dup Rat Modelsmentioning

confidence: 93%

Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes

Leone,

Zuglian,

Brambilla

et al. 2024

Front. Pharmacol.

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Neurodevelopmental disorders (NDDs) include a broad spectrum of pathological conditions that affect >4% of children worldwide, share common features and present a variegated genetic origin. They include clinically defined diseases, such as autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), motor disorders such as Tics and Tourette’s syndromes, but also much more heterogeneous conditions like intellectual disability (ID) and epilepsy. Schizophrenia (SCZ) has also recently been proposed to belong to NDDs. Relatively common causes of NDDs are copy number variations (CNVs), characterised by the gain or the loss of a portion of a chromosome. In this review, we focus on deletions and duplications at the 16p11.2 chromosomal region, associated with NDDs, ID, ASD but also epilepsy and SCZ. Some of the core phenotypes presented by human carriers could be recapitulated in animal and cellular models, which also highlighted prominent neurophysiological and signalling alterations underpinning 16p11.2 CNVs-associated phenotypes. In this review, we also provide an overview of the genes within the 16p11.2 locus, including those with partially known or unknown function as well as non-coding RNAs. A particularly interesting interplay was observed between MVP and MAPK3 in modulating some of the pathological phenotypes associated with the 16p11.2 deletion. Elucidating their role in intracellular signalling and their functional links will be a key step to devise novel therapeutic strategies for 16p11.2 CNVs-related syndromes.

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“…In this same line, the contribution to the phenotype of each gene within the deleted region could also be detailed, as it has been done to identify the contribution of Kctd13 gene to the cognitive impairment phenotype (Arbogast et al, 2019;Martin Lorenzo et al, 2021). To ascertain the robustness of these findings, a cross-species comparison should be conducted in the rat model (Martin Lorenzo et al, 2023), as recommended in recent guidelines to increase the value and robustness of preclinical models (Silverman et al, 2022). Rescue strategies could then be attempted, with for instance R-baclofen, a GABAb agonist, or Fasudil, an inhibitor of the Rho-associated protein kinase, both restoring the cognitive deficits in the mouse model (Stoppel et al, 2018;Martin Lorenzo et al, 2021).…”

Section: Perspectivesmentioning

confidence: 99%

Day-to-day spontaneous social behaviours is quantitatively and qualitatively affected in a 16p11.2 deletion mouse model

Rusu

Chevalier

Chaumont

et al. 2022

Preprint

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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. Based on previous study (Arbogast et al. 2016 PLoS genetics), we selected the mouse model of 16p11.2 deletion on a hybrid C57BL/6NxC3B genetic background to itemize the social deficits. We examined whether behavioural deficits observed in short observation periods were representative of the phenotype displayed by the same mice over long-term monitoring. We recorded the individual and social behaviours of 16p11.2 Del/+ mice and their wild-type littermates from both sexes in short-term (15 min) and 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 activity compared to wild-type littermates only over long-term monitoring. In the social domain, Del/+ mice of both sexes displayed only limited impairments over short-term monitoring, and more visible deficits over long-term monitoring. When recorded in quartets of familiar individuals, social impairments were stronger in males than in females. In pairs, significant perturbations of the organisation of the social communication and behaviours in Del/+ females appeared mostly over the long-term.ConclusionsAltogether, this suggests that social and contextual variations affect the phenotype of the 16p11.2 Del/+ mice differently in the activity and the social domains. The social behaviour was also differently affected between the two sexes. These findings confirm the importance of testing models both in short- and long-term conditions to provide a comprehensive view of their phenotype that will be more robust for pre-clinical targeted therapeutic trials.

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Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders

Cited by 3 publications

References 52 publications

Day-to-day spontaneous social behaviours is quantitatively and qualitatively affected in a 16p11.2 deletion mouse model

Day-to-day spontaneous social behaviours is quantitatively and qualitatively affected in a 16p11.2 deletion mouse model

Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes

Day-to-day spontaneous social behaviours is quantitatively and qualitatively affected in a 16p11.2 deletion mouse model

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