Cortical development dynamics across autism spectrum disorder mouse models

, phenotypic convergence across models may reveal common neurobiological processes in autism spectrum disorder (ASD). Here we profiled 251 samples from 11 monogenic mouse models of ASD using single-nucleus multi-omic sequencing across three developmental stages, both sexes and two brain regions. Despite genetic heterogeneity, ASD-linked mutations converged on perturbations of the radial glial cell lineage. These alterations reflect a transient developmental delay rather than lasting lineage misspecification and resolve by postnatal stages. Molecularly, the largest transcriptional differences emerged in neurons at early postnatal stages. These changes included downregulation of synaptic and ion channel-related genes, consistent with homeostatic adaptation or delayed maturation. Network analysis showed molecular convergence across models within each developmental stage, suggesting that diverse mutations linked to ASD impinge on common, stage-specific processes. Convergence becomes less pronounced by postnatal day 14, highlighting the dynamic nature of ASD-associated changes. Cross-genotype heterogeneity is superimposed on stage-specific effects. Electrophysiology corroborated this pattern: mutants generally showed altered neuronal excitability and synaptic properties with model-specific nuances. Our study also highlighted sex-specific gene expression alterations, with female mice often displaying larger effect sizes than male mice. Together, our findings provide a comprehensive view of developmental cellular and molecular dynamics across models of ASD.

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Publication Details

Journal
Nature
Published
2026-06-17
DOI
https://doi.org/10.1038/s41586-026-10679-1
Primary Topic
Autism Spectrum Disorder Research
Type
article
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article

Cortical development dynamics across autism spectrum disorder mouse models

Christoph Dotter, Daniel Malzl, Sabrina Ladstätter, Gintarė Sendžikaitė et al.
Nature
Autism Spectrum Disorder Research
article

Cortical development dynamics across autism spectrum disorder mouse models

Christoph Dotter, Daniel Malzl, Sabrina Ladstätter, Gintarė Sendžikaitė, Peter Koppensteiner, Tereza Bělinová, Chaitanya Chintaluri, Jörg Menche, Stephan Reichl, Peter V. Kharchenko, Satish Arcot Jayaram, Michela Lisi, Sarah Gorkiewicz, Gaia Novarino, Bernadette Basilico, Christoph Bock, Lena A. Schwarz, Sergey V. Isaev, Igor I. Adameyko, Tim P. Vogels, Christoph Bueschl, Christoph Sommer, Mohammad Goudarzi, Bárbara Oliveira, Matteo Barel
article en

Abstract

, phenotypic convergence across models may reveal common neurobiological processes in autism spectrum disorder (ASD). Here we profiled 251 samples from 11 monogenic mouse models of ASD using single-nucleus multi-omic sequencing across three developmental stages, both sexes and two brain regions. Despite genetic heterogeneity, ASD-linked mutations converged on perturbations of the radial glial cell lineage. These alterations reflect a transient developmental delay rather than lasting lineage misspecification and resolve by postnatal stages. Molecularly, the largest transcriptional differences emerged in neurons at early postnatal stages. These changes included downregulation of synaptic and ion channel-related genes, consistent with homeostatic adaptation or delayed maturation. Network analysis showed molecular convergence across models within each developmental stage, suggesting that diverse mutations linked to ASD impinge on common, stage-specific processes. Convergence becomes less pronounced by postnatal day 14, highlighting the dynamic nature of ASD-associated changes. Cross-genotype heterogeneity is superimposed on stage-specific effects. Electrophysiology corroborated this pattern: mutants generally showed altered neuronal excitability and synaptic properties with model-specific nuances. Our study also highlighted sex-specific gene expression alterations, with female mice often displaying larger effect sizes than male mice. Together, our findings provide a comprehensive view of developmental cellular and molecular dynamics across models of ASD.

Nature
University of Vienna (AT), Austrian Academy of Sciences (AT), Institute of Science and Technology Austria (AT), Austrian Research Institute for Artificial Intelligence (AT), Max Perutz Labs (AT), Karolinska Institutet (SE), Ludwig Boltzmann Institute for Age Research (AT), CeMM Research Center for Molecular Medicine (AT), Ludwig Boltzmann Institute Applied Diagnostics (AT), Vienna Biocenter (AT), Ludwig Boltzmann Institute for Cancer Research (AT), Medical University of Vienna (AT)
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Autism Spectrum Disorder Research
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