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Peer-reviewedCC BYNature

Cortical development dynamics across autism spectrum disorder mouse models

  • Lena A. Schwarz1
  • Christoph P. Dotter1
  • Sergey V. Isaev2
  • Michela Lisi1
  • Daniel Malzl3,4,5,6
  • Christoph Bueschl1
  • Sabrina Ladstätter3
  • Bárbara Oliveira1
  • Matteo Barel1
  • Bernadette Basilico1
  • Chaitanya Chintaluri1
  • Sarah Gorkiewicz1
13 more authors
  • Mohammad Goudarzi1
  • Tereza Bělinová1
  • Stephan Reichl3,7
  • Gintarė Sendžikaitė1
  • Satish Arcot Jayaram1
  • Peter Koppensteiner1
  • Christoph Sommer1
  • Tim P. Vogels1
  • Jörg Menche3,4,8,5,6
  • Igor I. Adameyko2,9
  • Peter V. Kharchenko1
  • Christoph Bock3,7
  • Gaia Novarino10
10 affiliations
  1. 1Institute of Science and Technology Austria, Klosterneuburg, Austria
  2. 2Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Vienna, Austria
  3. 3CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  4. 4Department of Structural and Computational Biology, Center for Molecular Biology, University of Vienna, Vienna, Austria
  5. 5Ludwig Boltzmann Institute for Network Medicine, University of Vienna, Vienna, Austria
  6. 6Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria
  7. 7Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria
  8. 8Faculty of Mathematics, University of Vienna, Vienna, Austria
  9. 9Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
  10. 10Institute of Science and Technology Austria, Klosterneuburg, Austria. [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{schwarz2026cortical,
  title = {{Cortical development dynamics across autism spectrum disorder mouse models}},
  author = {Lena A. Schwarz and Christoph P. Dotter and Sergey V. Isaev and Michela Lisi and Daniel Malzl and Christoph Bueschl and Sabrina Ladstätter and Bárbara Oliveira and Matteo Barel and Bernadette Basilico and Chaitanya Chintaluri and Sarah Gorkiewicz and Mohammad Goudarzi and Tereza Bělinová and Stephan Reichl and Gintarė Sendžikaitė and Satish Arcot Jayaram and Peter Koppensteiner and Christoph Sommer and Tim P. Vogels and Jörg Menche and Igor I. Adameyko and Peter V. Kharchenko and Christoph Bock and Gaia Novarino},
  journal = {Nature},
  year = {2026},
  month = jun,
  doi = {10.1038/s41586-026-10679-1},
  url = {https://doi.org/10.1038/s41586-026-10679-1},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cortical development dynamics across autism spectrum disorder mouse models
AU  - Lena A. Schwarz
AU  - Christoph P. Dotter
AU  - Sergey V. Isaev
AU  - Michela Lisi
AU  - Daniel Malzl
AU  - Christoph Bueschl
AU  - Sabrina Ladstätter
AU  - Bárbara Oliveira
AU  - Matteo Barel
AU  - Bernadette Basilico
AU  - Chaitanya Chintaluri
AU  - Sarah Gorkiewicz
AU  - Mohammad Goudarzi
AU  - Tereza Bělinová
AU  - Stephan Reichl
AU  - Gintarė Sendžikaitė
AU  - Satish Arcot Jayaram
AU  - Peter Koppensteiner
AU  - Christoph Sommer
AU  - Tim P. Vogels
AU  - Jörg Menche
AU  - Igor I. Adameyko
AU  - Peter V. Kharchenko
AU  - Christoph Bock
AU  - Gaia Novarino
PY  - 2026
DA  - 2026/06/17
JO  - Nature
DO  - 10.1038/s41586-026-10679-1
UR  - https://doi.org/10.1038/s41586-026-10679-1
AB  - , 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.
SN  - 0028-0836
SN  - 1476-4687
ER  -