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Background: Autism spectrum disorders affect more than 1% of the population, impairing social communication and increasing stereotyped behaviours. A microdeletion 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. Methods: To 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 longterm observation periods lasting several days and nights, to parallel everydaylife 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. Results: We 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. Discussion: Altogether, 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. [ABSTRACT FROM AUTHOR]

Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches. [ABSTRACT FROM AUTHOR]

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice. [ABSTRACT FROM AUTHOR]