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Opposite phenotypic effects and genetic dosage in mouse models of 16p11.2 deletion and duplication syndromes

ABSTRACT: The 16p11.2 deletion and duplication syndromes have been associated with developmental delay and autism spectrum disorders, and a reciprocal effect on body mass index. Here we explored these links with new engineered mouse models carrying a deletion (Del/+) and duplication (Dup/+) of the whole 16p11.2 homologous Sult1a1-Spn region. On a pure genetic background, compared to wild-types, Del/+ mice carrying the deletion showed weight and adipogenesis deficits, hyperactivity, repetitive behaviors, and recognition memory deficits, whereas Dup/+ mice showed the opposite phenotypes and Del/Dup individuals displayed no changes. Alterations in social interaction were also observed in Del/+ and Dup/+ animals on a mixed genetic background. Transcriptomic analysis revealed that the majority of genes located on the Sult1a1-Spn were dosage-sensitive and potentially implicated in the opposite phenotypes described above on the neurocognitive aspect. Nevertheless, the outcome of the 16p11 region genetic dosage on metabolism depends on different genetic contributions between human and mouse.

ORGANISM(S): Mus musculus

PROVIDER: GSE66468 | GEO | 2015/11/18

SECONDARY ACCESSION(S): PRJNA277022

REPOSITORIES: GEO

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Excitatory dysfunction drives network and calcium handling deficits in 16p11.2 duplication schizophrenia iPSC-derived neurons

Project description:Background - Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human iPSC-derived neurons (iNs) has emerged as a promising strategy. Copy number variations (CNV) confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing risk 14.5 fold. Methods - To dissect the contribution of excitatory (iENs) versus GABAergic (iGNs) neurons to SCZ pathophysiology, we induced iNs from CRISPR-Cas9 engineered isogenic and SCZ patient-derived iPSCs, and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. Results - In iEN/iGN cocultures, we found reduced neuronal network firing rate and synchrony at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for excitatory neurons. Transcriptomic analysis of isogenic 16p11.2 duplication (DUP) iENs revealed pathway dysregulation related to neuroarchitecture and calcium ion binding. Consistent with this, isogenic DUP iENs showed reduced dendrite length and calcium imaging revealed deficits in calcium handling. Analysis of iENs from 16p11.2 duplication-carrying SCZ patients (SCZ) revealed overlapping deficits in network synchrony, dendrite arborization and calcium handling. Conclusions - Our results indicate 16p11.2 duplication-dependent alterations to SCZ neurodevelopment. Calcium ion binding was the only altered transcriptomic gene set shared between isogenic and patient-derived iENs, suggesting a central role of calcium signaling in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers and supports network synchrony and calcium handling as outcomes directly linked to this genetic mutation.

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Project description:Opposite phenotypic effects and genetic dosage in mouse models of 16p11.2 deletion and duplication syndromes

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