[{"publication_status":"epub_ahead","author":[{"first_name":"Lena A","full_name":"Schwarz, Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87","last_name":"Schwarz"},{"full_name":"Dotter, Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","last_name":"Dotter","orcid":"0000-0002-9033-9096","first_name":"Christoph"},{"last_name":"Isaev","full_name":"Isaev, Sergey","first_name":"Sergey"},{"first_name":"Michela","full_name":"Lisi, Michela","id":"39383c1b-d3eb-11ef-8d6c-c8cdf4e10c8c","last_name":"Lisi"},{"first_name":"Daniel","last_name":"Malzl","full_name":"Malzl, Daniel"},{"last_name":"Büschl","full_name":"Büschl, Christoph","id":"2a8c054c-0913-11ee-9159-f8ef515809ed","first_name":"Christoph"},{"last_name":"Ladstätter","full_name":"Ladstätter, Sabrina","first_name":"Sabrina"},{"last_name":"Oliveira","full_name":"Oliveira, Bárbara","id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","first_name":"Bárbara"},{"last_name":"Barel","full_name":"Barel, Matteo","id":"8959927b-2236-11ed-bd6e-ea83d94ade0e","first_name":"Matteo"},{"first_name":"Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","full_name":"Basilico, Bernadette"},{"first_name":"Chaitanya","orcid":"0000-0003-4252-1608","last_name":"Chintaluri","id":"BA06AFEE-A4BA-11EA-AE5C-14673DDC885E","full_name":"Chintaluri, Chaitanya"},{"first_name":"Sarah","id":"f141a35d-15a9-11ec-9fb2-fef6becc7b6f","full_name":"Gorkiewicz, Sarah","last_name":"Gorkiewicz"},{"first_name":"Mohammad","full_name":"Goudarzi, Mohammad","id":"3384113A-F248-11E8-B48F-1D18A9856A87","last_name":"Goudarzi"},{"full_name":"Belinova, Tereza","id":"0bf89b6a-d28b-11eb-8bd6-f43768e4d368","last_name":"Belinova","first_name":"Tereza"},{"last_name":"Reichl","full_name":"Reichl, Stephan","first_name":"Stephan"},{"last_name":"Sendžikaitė","full_name":"Sendžikaitė, Gintarė","id":"dd6d52f2-c50d-11eb-9548-bcf0ff82b344","first_name":"Gintarė"},{"last_name":"Arcot Jayaram","full_name":"Arcot Jayaram, Satish","id":"b0bbee33-09f7-11eb-909c-8b358058d28a","first_name":"Satish","orcid":"0000-0002-2479-2669"},{"full_name":"Koppensteiner, Peter","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","last_name":"Koppensteiner","orcid":"0000-0002-3509-1948","first_name":"Peter"},{"full_name":"Sommer, Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","last_name":"Sommer","orcid":"0000-0003-1216-9105","first_name":"Christoph M"},{"last_name":"Vogels","id":"CB6FF8D2-008F-11EA-8E08-2637E6697425","full_name":"Vogels, Tim P","first_name":"Tim P","orcid":"0000-0003-3295-6181"},{"first_name":"Jörg","full_name":"Menche, Jörg","last_name":"Menche"},{"full_name":"Adameyko, Igor","last_name":"Adameyko","first_name":"Igor"},{"first_name":"Peter Vasili","last_name":"Kharchenko","id":"0095641e-7eb7-11f1-8665-aec51a2ab5e0","full_name":"Kharchenko, Peter Vasili"},{"last_name":"Bock","full_name":"Bock, Christoph","first_name":"Christoph"},{"first_name":"Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia"}],"abstract":[{"lang":"eng","text":"Despite the functional diversity of over 100 causal genes1,2,3, 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."}],"project":[{"name":"Toward an understanding of the brain interstitial system and the extracellular proteome in health and autism spectrum disorders","grant_number":"101044865","_id":"34ba8964-11ca-11ed-8bc3-e15864e7e9a6"},{"name":"Critical windows and reversibility of ASD associated with mutations in chromatin remodelers","grant_number":"707964","_id":"9B91375C-BA93-11EA-9121-9846C619BF3A"},{"_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Molecular Drug Targets","grant_number":"W1232"},{"_id":"ebb38b5d-77a9-11ec-83b8-a42e08120a88","grant_number":"FG1803 49015","name":"Neurobiology of anxiety in autism spectrum disorders"}],"fulldoi":"https://doi.org/10.1038/s41586-026-10679-1","oa_version":"Published Version","date_published":"2026-06-17T00:00:00Z","doi":"10.1038/s41586-026-10679-1","quality_controlled":"1","researchdata_availability":"yes","status":"public","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","_id":"22295","OA_type":"hybrid","year":"2026","publication":"Nature","citation":{"ieee":"L. A. Schwarz <i>et al.</i>, “Cortical development dynamics across autism spectrum disorder mouse models,” <i>Nature</i>. Springer Nature, 2026.","apa":"Schwarz, L. A., Dotter, C., Isaev, S., Lisi, M., Malzl, D., Büschl, C., … Novarino, G. (2026). Cortical development dynamics across autism spectrum disorder mouse models. <i>Nature</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41586-026-10679-1\">https://doi.org/10.1038/s41586-026-10679-1</a>","ista":"Schwarz LA, Dotter C, Isaev S, Lisi M, Malzl D, Büschl C, Ladstätter S, Oliveira B, Barel M, Basilico B, Chintaluri C, Gorkiewicz S, Goudarzi M, Belinova T, Reichl S, Sendžikaitė G, Arcot Jayaram S, Koppensteiner P, Sommer CM, Vogels TP, Menche J, Adameyko I, Kharchenko PV, Bock C, Novarino G. 2026. Cortical development dynamics across autism spectrum disorder mouse models. Nature.","short":"L.A. Schwarz, C. Dotter, S. Isaev, M. Lisi, D. Malzl, C. Büschl, S. Ladstätter, B. Oliveira, M. Barel, B. Basilico, C. Chintaluri, S. Gorkiewicz, M. Goudarzi, T. Belinova, S. Reichl, G. Sendžikaitė, S. Arcot Jayaram, P. Koppensteiner, C.M. Sommer, T.P. Vogels, J. Menche, I. Adameyko, P.V. Kharchenko, C. Bock, G. Novarino, Nature (2026).","mla":"Schwarz, Lena A., et al. “Cortical Development Dynamics across Autism Spectrum Disorder Mouse Models.” <i>Nature</i>, Springer Nature, 2026, doi:<a href=\"https://doi.org/10.1038/s41586-026-10679-1\">10.1038/s41586-026-10679-1</a>.","chicago":"Schwarz, Lena A, Christoph Dotter, Sergey Isaev, Michela Lisi, Daniel Malzl, Christoph Büschl, Sabrina Ladstätter, et al. “Cortical Development Dynamics across Autism Spectrum Disorder Mouse Models.” <i>Nature</i>. Springer Nature, 2026. <a href=\"https://doi.org/10.1038/s41586-026-10679-1\">https://doi.org/10.1038/s41586-026-10679-1</a>.","ama":"Schwarz LA, Dotter C, Isaev S, et al. Cortical development dynamics across autism spectrum disorder mouse models. <i>Nature</i>. 2026. doi:<a href=\"https://doi.org/10.1038/s41586-026-10679-1\">10.1038/s41586-026-10679-1</a>"},"external_id":{"pmid":["42310454"]},"article_processing_charge":"Yes (via OA deal)","PlanS_conform":"1","language":[{"iso":"eng"}],"main_file_link":[{"url":"https://doi.org/10.1038/s41586-026-10679-1","open_access":"1"}],"department":[{"_id":"AnKi"},{"_id":"GaNo"},{"_id":"TiVo"},{"_id":"ScienComp"},{"_id":"GradSch"},{"_id":"Bio"},{"_id":"PreCl"}],"dataavailabilitystatement":"Single-nucleus multiomics data are available from the Gene Expression Omnibus (GSE328363). The mm10 reference genome was used for the alignment (refdata-cellranger-arc-mm10-2020-A-2.0.0, obtained from https://cf.10xgenomics.com/supp/cell-arc/refdata-cellranger-arc-mm10-2020-A-2.0.0.tar.gz). Single-cell data can be accessed and visualized through a CELLxGENE database (https://adameykolab.hifo.meduniwien.ac.at/cellxgene_public/filecrawl/.2026_Nature_Schwarz). Source data are provided with this paper. Scripts and analyses that support the main findings of this study are accessible in a GitHub repository (https://git.ista.ac.at/research-sofware/mouseome).","supplementarymaterial":"yes","type":"journal_article","month":"06","ddc":["570"],"acknowledgement":"We thank F. Freeman, V. Voronin and M. Ladron de Guevara for technical assistance; A. Stichelberger and S. Liegenfeld for the management of our animal colony; M. Schunn, C. Gold and the Preclinical Facility team for technical assistance; C. Jansen and the Scientific Computing Facility for bioinformatics support and technical assistance; the Biomedical Sequencing Facility at CeMM for assistance with next-generation sequencing; and J. Lin and T. Krausgruber in the laboratory of C. Bock for support with flow cytometry; J. Kirchner for illustrating the multi-omics approach depicted in Fig. 1; and all members of the laboratory of G.N. for their support and discussions. This study was supported by the Scientific Service Units of ISTA through resources provided by the Imaging & Optics Facility and the Laboratory Support Facility. Bulk RNA-seq was performed by the Next Generation Sequencing Facility at Vienna BioCenter Core Facilities, member of the Vienna BioCenter. This work was supported by a European Research Council Consolidator Grant (PR1028ERC02), by SFARI (PR1028SIM02) and by the Austrian Science Fund (PE1028W1232 and PR1028FG1803) to G.N. Open access funding provided by Institute of Science and Technology (IST Austria).","article_type":"original","pmid":1,"license":"https://creativecommons.org/licenses/by/4.0/","date_created":"2026-07-13T09:47:21Z","publisher":"Springer Nature","publication_identifier":{"issn":["0028-0836"],"eissn":["1476-4687"]},"scopus_import":"1","OA_place":"publisher","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"corr_author":"1","has_accepted_license":"1","title":"Cortical development dynamics across autism spectrum disorder mouse models","date_updated":"2026-08-04T09:29:55Z","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"day":"17","related_material":{"link":[{"url":"https://ista.ac.at/en/news/patterns-in-genetic-chaos/","relation":"press_release","description":"News on ISTA website"}]},"oa":1},{"doi":"10.1038/s41586-025-08985-1","quality_controlled":"1","fulldoi":"https://doi.org/10.1038/s41586-025-08985-1","isi":1,"oa_version":"Published Version","date_published":"2025-06-12T00:00:00Z","project":[{"name":"Studying Organelle Structure and Function at Nanoscale Resolution with Expansion Microscopy","grant_number":"26137","_id":"6285a163-2b32-11ec-9570-8e204ca2dba5"},{"name":"International IST Doctoral Program","grant_number":"665385","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"name":"Toward an understanding of the brain interstitial system and the extracellular proteome in health and autism spectrum disorders","grant_number":"101044865","_id":"34ba8964-11ca-11ed-8bc3-e15864e7e9a6"},{"call_identifier":"FWF","_id":"26AA4EF2-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets","grant_number":"W1232-B24"}],"publication_status":"published","author":[{"orcid":"0000-0002-7667-6854","first_name":"Mojtaba","id":"3A0A06F4-F248-11E8-B48F-1D18A9856A87","full_name":"Tavakoli, Mojtaba","last_name":"Tavakoli"},{"first_name":"Julia","last_name":"Lyudchik","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","full_name":"Lyudchik, Julia"},{"full_name":"Januszewski, Michał","last_name":"Januszewski","first_name":"Michał"},{"id":"7e146587-8972-11ed-ae7b-d7a32ea86a81","full_name":"Vistunou, Vitali","last_name":"Vistunou","first_name":"Vitali"},{"first_name":"Nathalie","id":"40E7F008-F248-11E8-B48F-1D18A9856A87","full_name":"Agudelo Duenas, Nathalie","last_name":"Agudelo Duenas"},{"last_name":"Vorlaufer","id":"937696FA-C996-11E9-8C7C-CF13E6697425","full_name":"Vorlaufer, Jakob","first_name":"Jakob","orcid":"0009-0000-7590-3501"},{"first_name":"Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer","full_name":"Sommer, Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Kreuzinger","full_name":"Kreuzinger, Caroline","id":"382077BA-F248-11E8-B48F-1D18A9856A87","first_name":"Caroline"},{"id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","full_name":"Oliveira, Bárbara","last_name":"Oliveira","first_name":"Bárbara"},{"id":"9ac8f577-2357-11eb-997a-e566c5550886","full_name":"Cenameri, Alban","last_name":"Cenameri","first_name":"Alban"},{"full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","orcid":"0000-0002-7673-7178","first_name":"Gaia"},{"full_name":"Jain, Viren","last_name":"Jain","first_name":"Viren"},{"first_name":"Johann G","orcid":"0000-0001-8559-3973","last_name":"Danzl","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","full_name":"Danzl, Johann G"}],"intvolume":"       642","abstract":[{"lang":"eng","text":"The information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution1,2 with dense cellular labelling. Light microscopy is uniquely positioned to visualize specific molecules, but dense, synapse-level circuit reconstruction by light microscopy has been out of reach, owing to limitations in resolution, contrast and volumetric imaging capability. Here we describe light-microscopy-based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning-based segmentation and analysis of connectivity, thereby directly incorporating molecular information into synapse-level reconstructions of brain tissue. LICONN will allow synapse-level phenotyping of brain tissue in biological experiments in a readily adoptable manner."}],"citation":{"ama":"Tavakoli M, Lyudchik J, Januszewski M, et al. Light-microscopy-based connectomic reconstruction of mammalian brain tissue. <i>Nature</i>. 2025;642:398-410. doi:<a href=\"https://doi.org/10.1038/s41586-025-08985-1\">10.1038/s41586-025-08985-1</a>","short":"M. Tavakoli, J. Lyudchik, M. Januszewski, V. Vistunou, N. Agudelo Duenas, J. Vorlaufer, C.M. Sommer, C. Kreuzinger, B. Oliveira, A. Cenameri, G. Novarino, V. Jain, J.G. Danzl, Nature 642 (2025) 398–410.","mla":"Tavakoli, Mojtaba, et al. “Light-Microscopy-Based Connectomic Reconstruction of Mammalian Brain Tissue.” <i>Nature</i>, vol. 642, Springer Nature, 2025, pp. 398–410, doi:<a href=\"https://doi.org/10.1038/s41586-025-08985-1\">10.1038/s41586-025-08985-1</a>.","chicago":"Tavakoli, Mojtaba, Julia Lyudchik, Michał Januszewski, Vitali Vistunou, Nathalie Agudelo Duenas, Jakob Vorlaufer, Christoph M Sommer, et al. “Light-Microscopy-Based Connectomic Reconstruction of Mammalian Brain Tissue.” <i>Nature</i>. Springer Nature, 2025. <a href=\"https://doi.org/10.1038/s41586-025-08985-1\">https://doi.org/10.1038/s41586-025-08985-1</a>.","apa":"Tavakoli, M., Lyudchik, J., Januszewski, M., Vistunou, V., Agudelo Duenas, N., Vorlaufer, J., … Danzl, J. G. (2025). Light-microscopy-based connectomic reconstruction of mammalian brain tissue. <i>Nature</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41586-025-08985-1\">https://doi.org/10.1038/s41586-025-08985-1</a>","ista":"Tavakoli M, Lyudchik J, Januszewski M, Vistunou V, Agudelo Duenas N, Vorlaufer J, Sommer CM, Kreuzinger C, Oliveira B, Cenameri A, Novarino G, Jain V, Danzl JG. 2025. Light-microscopy-based connectomic reconstruction of mammalian brain tissue. Nature. 642, 398–410.","ieee":"M. Tavakoli <i>et al.</i>, “Light-microscopy-based connectomic reconstruction of mammalian brain tissue,” <i>Nature</i>, vol. 642. Springer Nature, pp. 398–410, 2025."},"external_id":{"pmid":["40335689"],"isi":["001483477000001"]},"article_processing_charge":"Yes (via OA deal)","PlanS_conform":"1","publication":"Nature","year":"2025","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","status":"public","_id":"19704","OA_type":"hybrid","OA_place":"publisher","file_date_updated":"2025-07-03T06:55:20Z","scopus_import":"1","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"ScienComp"},{"_id":"PreCl"},{"_id":"M-Shop"},{"_id":"E-Lib"}],"corr_author":"1","has_accepted_license":"1","publisher":"Springer Nature","publication_identifier":{"eissn":["1476-4687"],"issn":["0028-0836"]},"ec_funded":1,"ddc":["570"],"month":"06","type":"journal_article","volume":642,"acknowledgement":"We thank S. Dorkenwald and P. Li for critical reading of the manuscript, S. Loomba for discussions and E. Miguel for support with data handling. We acknowledge support from ISTA’s scientific service units: Imaging and Optics, Lab Support, Scientific Computing, the preclinical facility, the Miba Machine Shop and the library. We acknowledge funding from the following sources: Austrian Science Fund (FWF) grant DK W1232 (J.G.D. and M.R.T.); Austrian Academy of Sciences DOC fellowship 26137 (M.R.T.); Gesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022 (J.G.D.); the European Union’s Horizon 2020 research and innovation programme and Marie Skłodowska-Curie Actions Fellowship 665385 (J.L.); and the European Union’s Horizon 2020 research and innovation programme and European Research Council (ERC) grant 101044865 ‘SecretAutism’ (G.N.).Open access funding provided by Institute of Science and Technology (IST Austria).","article_type":"original","date_created":"2025-05-18T22:02:51Z","pmid":1,"page":"398-410","language":[{"iso":"eng"}],"department":[{"_id":"JoDa"},{"_id":"GradSch"},{"_id":"Bio"},{"_id":"GaNo"}],"file":[{"creator":"dernst","file_name":"2025_Nature_Tavakoli.pdf","access_level":"open_access","date_created":"2025-07-03T06:55:20Z","success":1,"date_updated":"2025-07-03T06:55:20Z","checksum":"ebc99d7108e728f46db0a009292675ef","file_size":133201290,"file_id":"19959","relation":"main_file","content_type":"application/pdf"}],"oa":1,"day":"12","related_material":{"record":[{"status":"public","id":"18697","relation":"research_data"},{"relation":"earlier_version","id":"18677","status":"public"}],"link":[{"url":"https://ista.ac.at/en/news/piecing-together-the-brain-puzzle/","relation":"press_release","description":"News on ISTA website"}]},"date_updated":"2026-10-02T09:59:44Z","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"title":"Light-microscopy-based connectomic reconstruction of mammalian brain tissue"},{"year":"2024","status":"public","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","_id":"18677","citation":{"short":"M. Tavakoli, J. Lyudchik, M. Januszewski, V. Vistunou, N. Agudelo Duenas, J. Vorlaufer, C.M. Sommer, C. Kreuzinger, B. Oliveira, A. Cenameri, G. Novarino, V. Jain, J.G. Danzl, BioRxiv (n.d.).","mla":"Tavakoli, Mojtaba, et al. “Light-Microscopy Based Dense Connectomic Reconstruction of Mammalian Brain Tissue.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.1101/2024.03.01.582884\">10.1101/2024.03.01.582884</a>.","chicago":"Tavakoli, Mojtaba, Julia Lyudchik, Michał Januszewski, Vitali Vistunou, Nathalie Agudelo Duenas, Jakob Vorlaufer, Christoph M Sommer, et al. “Light-Microscopy Based Dense Connectomic Reconstruction of Mammalian Brain Tissue.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.1101/2024.03.01.582884\">https://doi.org/10.1101/2024.03.01.582884</a>.","ieee":"M. Tavakoli <i>et al.</i>, “Light-microscopy based dense connectomic reconstruction of mammalian brain tissue,” <i>bioRxiv</i>. .","ista":"Tavakoli M, Lyudchik J, Januszewski M, Vistunou V, Agudelo Duenas N, Vorlaufer J, Sommer CM, Kreuzinger C, Oliveira B, Cenameri A, Novarino G, Jain V, Danzl JG. Light-microscopy based dense connectomic reconstruction of mammalian brain tissue. bioRxiv, <a href=\"https://doi.org/10.1101/2024.03.01.582884\">10.1101/2024.03.01.582884</a>.","apa":"Tavakoli, M., Lyudchik, J., Januszewski, M., Vistunou, V., Agudelo Duenas, N., Vorlaufer, J., … Danzl, J. G. (n.d.). Light-microscopy based dense connectomic reconstruction of mammalian brain tissue. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2024.03.01.582884\">https://doi.org/10.1101/2024.03.01.582884</a>","ama":"Tavakoli M, Lyudchik J, Januszewski M, et al. Light-microscopy based dense connectomic reconstruction of mammalian brain tissue. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2024.03.01.582884\">10.1101/2024.03.01.582884</a>"},"article_processing_charge":"No","publication":"bioRxiv","project":[{"name":"Studying Organelle Structure and Function at Nanoscale Resolution with Expansion Microscopy","grant_number":"26137","_id":"6285a163-2b32-11ec-9570-8e204ca2dba5"},{"name":"International IST Doctoral Program","grant_number":"665385","call_identifier":"H2020","_id":"2564DBCA-B435-11E9-9278-68D0E5697425"},{"name":"Toward an understanding of the brain interstitial system and the extracellular proteome in health and autism spectrum disorders","grant_number":"101044865","_id":"34ba8964-11ca-11ed-8bc3-e15864e7e9a6"},{"call_identifier":"FWF","_id":"26AA4EF2-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets","grant_number":"W1232-B24"}],"fulldoi":"https://doi.org/10.1101/2024.03.01.582884","oa_version":"Preprint","date_published":"2024-07-08T00:00:00Z","publication_status":"draft","author":[{"last_name":"Tavakoli","full_name":"Tavakoli, Mojtaba","id":"3A0A06F4-F248-11E8-B48F-1D18A9856A87","first_name":"Mojtaba","orcid":"0000-0002-7667-6854"},{"id":"46E28B80-F248-11E8-B48F-1D18A9856A87","full_name":"Lyudchik, Julia","last_name":"Lyudchik","first_name":"Julia"},{"first_name":"Michał","last_name":"Januszewski","full_name":"Januszewski, Michał"},{"id":"7e146587-8972-11ed-ae7b-d7a32ea86a81","full_name":"Vistunou, Vitali","last_name":"Vistunou","first_name":"Vitali"},{"first_name":"Nathalie","last_name":"Agudelo Duenas","full_name":"Agudelo Duenas, Nathalie","id":"40E7F008-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Vorlaufer","full_name":"Vorlaufer, Jakob","id":"937696FA-C996-11E9-8C7C-CF13E6697425","first_name":"Jakob","orcid":"0009-0000-7590-3501"},{"orcid":"0000-0003-1216-9105","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","full_name":"Sommer, Christoph M","last_name":"Sommer"},{"first_name":"Caroline","full_name":"Kreuzinger, Caroline","id":"382077BA-F248-11E8-B48F-1D18A9856A87","last_name":"Kreuzinger"},{"first_name":"Bárbara","id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","full_name":"Oliveira, Bárbara","last_name":"Oliveira"},{"first_name":"Alban","last_name":"Cenameri","full_name":"Cenameri, Alban","id":"9ac8f577-2357-11eb-997a-e566c5550886"},{"orcid":"0000-0002-7673-7178","first_name":"Gaia","full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino"},{"full_name":"Jain, Viren","last_name":"Jain","first_name":"Viren"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","full_name":"Danzl, Johann G","last_name":"Danzl","orcid":"0000-0001-8559-3973","first_name":"Johann G"}],"abstract":[{"lang":"eng","text":"The information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution with dense cellular labeling. Light microscopy is uniquely positioned to visualize specific molecules but dense, synapse-level circuit reconstruction by light microscopy has been out of reach due to limitations in resolution, contrast, and volumetric imaging capability. Here we developed light-microscopy based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning based segmentation and analysis of connectivity, thus directly incorporating molecular information in synapse-level brain tissue reconstructions. LICONN will allow synapse-level brain tissue phenotyping in biological experiments in a readily adoptable manner."}],"researchdata_availability":"no","doi":"10.1101/2024.03.01.582884","date_updated":"2026-10-02T11:27:43Z","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"title":"Light-microscopy based dense connectomic reconstruction of mammalian brain tissue","das_tickbox":"0","oa":1,"day":"08","related_material":{"record":[{"id":"19704","relation":"later_version","status":"public"},{"relation":"dissertation_contains","id":"18674","status":"public"},{"id":"18681","relation":"dissertation_contains","status":"public"}]},"month":"07","supplementarymaterial":"no","type":"preprint","acknowledgement":"We thank Sven Dorkenwald and Peter Li for critical reading of the\r\nmanuscript. We acknowledge expert support by ISTA’s scientific service units: Imaging and\r\nOptics, Lab Support, Scientific Computing, Preclinical Facility, Miba Machine Shop, and Library.\r\nWe gratefully acknowledge funding by the following sources:\r\nAustrian Science Fund (FWF) grant DK W1232 (JGD, MRT)\r\nAustrian Academy of Sciences DOC fellowship 26137 (MRT)\r\nEU Horizon 2020 program, Marie Skłodowska-Curie Actions Fellowship 665385 (JL)\r\nGesellschaft für Forschungsförderung NÖ (NFB) grant LSC18-022 (JGD)\r\nEuropean Union’s Horizon 2020 research and innovation programme, European Research\r\nCouncil (ERC) grant 101044865 “SecretAutism.”\r\n","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","date_created":"2024-12-18T14:48:24Z","language":[{"iso":"eng"}],"main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/2024.03.01.582884"}],"department":[{"_id":"GaNo"},{"_id":"JoDa"}],"OA_place":"repository","acknowledged_ssus":[{"_id":"E-Lib"},{"_id":"M-Shop"},{"_id":"LifeSc"},{"_id":"Bio"},{"_id":"ScienComp"}],"corr_author":"1","ec_funded":1},{"fulldoi":"https://doi.org/10.1016/j.celrep.2022.110615","project":[{"name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508","call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425"},{"name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy","grant_number":"I04205","call_identifier":"FWF","_id":"2690FEAC-B435-11E9-9278-68D0E5697425"}],"isi":1,"date_published":"2022-04-05T00:00:00Z","oa_version":"Published Version","abstract":[{"lang":"eng","text":"Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency affects neurodevelopmental is unclear. Here, employing human cerebral organoids, we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories with an accelerated and delayed generation of, respectively, inhibitory and excitatory neurons that yields, at days 60 and 120, symmetrically opposite expansions in their proportions. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patients’ macrocephaly. Through an isogenic design of patient-specific mutations and mosaic organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Our results define cell-type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations, our study uncovers reproducible developmental alterations that may be employed for neurodevelopmental disease modeling."}],"intvolume":"        39","publication_status":"published","issue":"1","author":[{"last_name":"Villa","full_name":"Villa, Carlo Emanuele","first_name":"Carlo Emanuele"},{"full_name":"Cheroni, Cristina","last_name":"Cheroni","first_name":"Cristina"},{"orcid":"0000-0002-9033-9096","first_name":"Christoph","full_name":"Dotter, Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","last_name":"Dotter"},{"first_name":"Alejandro","full_name":"López-Tóbon, Alejandro","last_name":"López-Tóbon"},{"id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","full_name":"Oliveira, Bárbara","last_name":"Oliveira","first_name":"Bárbara"},{"last_name":"Sacco","id":"42C9F57E-F248-11E8-B48F-1D18A9856A87","full_name":"Sacco, Roberto","first_name":"Roberto"},{"first_name":"Aysan Çerağ","last_name":"Yahya","full_name":"Yahya, Aysan Çerağ","id":"365A65F8-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Jasmin","full_name":"Morandell, Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","last_name":"Morandell"},{"last_name":"Gabriele","full_name":"Gabriele, Michele","first_name":"Michele"},{"last_name":"Tavakoli","id":"3A0A06F4-F248-11E8-B48F-1D18A9856A87","full_name":"Tavakoli, Mojtaba","first_name":"Mojtaba","orcid":"0000-0002-7667-6854"},{"last_name":"Lyudchik","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","full_name":"Lyudchik, Julia","first_name":"Julia"},{"orcid":"0000-0003-1216-9105","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","full_name":"Sommer, Christoph M","last_name":"Sommer"},{"first_name":"Mariano","last_name":"Gabitto","full_name":"Gabitto, Mariano"},{"full_name":"Danzl, Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","orcid":"0000-0001-8559-3973","first_name":"Johann G"},{"last_name":"Testa","full_name":"Testa, Giuseppe","first_name":"Giuseppe"},{"orcid":"0000-0002-7673-7178","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","last_name":"Novarino"}],"doi":"10.1016/j.celrep.2022.110615","quality_controlled":"1","year":"2022","keyword":["General Biochemistry","Genetics and Molecular Biology"],"status":"public","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","_id":"11160","external_id":{"pmid":["35385734"],"isi":["000785983900003"]},"article_processing_charge":"Yes","citation":{"short":"C.E. Villa, C. Cheroni, C. Dotter, A. López-Tóbon, B. Oliveira, R. Sacco, A.Ç. Yahya, J. Morandell, M. Gabriele, M. Tavakoli, J. Lyudchik, C.M. Sommer, M. Gabitto, J.G. Danzl, G. Testa, G. Novarino, Cell Reports 39 (2022).","mla":"Villa, Carlo Emanuele, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” <i>Cell Reports</i>, vol. 39, no. 1, 110615, Elsevier, 2022, doi:<a href=\"https://doi.org/10.1016/j.celrep.2022.110615\">10.1016/j.celrep.2022.110615</a>.","chicago":"Villa, Carlo Emanuele, Cristina Cheroni, Christoph Dotter, Alejandro López-Tóbon, Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” <i>Cell Reports</i>. Elsevier, 2022. <a href=\"https://doi.org/10.1016/j.celrep.2022.110615\">https://doi.org/10.1016/j.celrep.2022.110615</a>.","apa":"Villa, C. E., Cheroni, C., Dotter, C., López-Tóbon, A., Oliveira, B., Sacco, R., … Novarino, G. (2022). CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. <i>Cell Reports</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.celrep.2022.110615\">https://doi.org/10.1016/j.celrep.2022.110615</a>","ista":"Villa CE, Cheroni C, Dotter C, López-Tóbon A, Oliveira B, Sacco R, Yahya AÇ, Morandell J, Gabriele M, Tavakoli M, Lyudchik J, Sommer CM, Gabitto M, Danzl JG, Testa G, Novarino G. 2022. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. 39(1), 110615.","ieee":"C. E. Villa <i>et al.</i>, “CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories,” <i>Cell Reports</i>, vol. 39, no. 1. Elsevier, 2022.","ama":"Villa CE, Cheroni C, Dotter C, et al. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. <i>Cell Reports</i>. 2022;39(1). doi:<a href=\"https://doi.org/10.1016/j.celrep.2022.110615\">10.1016/j.celrep.2022.110615</a>"},"article_number":"110615","publication":"Cell Reports","volume":39,"acknowledgement":"We thank Farnaz Freeman for technical assistance. This research was supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Bioimaging Facility (BIF) and the Life Science Facility (LSF). This work supported by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 to G.N. (REVERSEAUTISM) and grant 825759 to G.T. (ENDpoiNTs); the Fondazione Cariplo 2017-0886 to A.L.T.; E-Rare-3 JTC 2018 IMPACT to M. Gabriele; and the Austrian Science Fund FWF I 4205-B to G.N. Graphical abstract and figures were created using BioRender.com.","article_type":"original","date_created":"2022-04-15T09:03:10Z","pmid":1,"type":"journal_article","ddc":["570"],"month":"04","file":[{"file_name":"2022_CellReports_Villa.pdf","creator":"dernst","date_updated":"2022-04-15T09:06:25Z","success":1,"date_created":"2022-04-15T09:06:25Z","access_level":"open_access","file_size":"7808644","file_id":"11164","checksum":"b4e8d68f0268dec499af333e6fd5d8e1","content_type":"application/pdf","relation":"main_file"}],"language":[{"iso":"eng"}],"department":[{"_id":"JoDa"},{"_id":"GaNo"}],"has_accepted_license":"1","file_date_updated":"2022-04-15T09:06:25Z","scopus_import":"1","corr_author":"1","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"publication_identifier":{"issn":["2211-1247"]},"ec_funded":1,"publisher":"Elsevier","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_updated":"2026-10-28T23:30:08Z","title":"CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories","oa":1,"related_material":{"record":[{"relation":"dissertation_contains","id":"18674","status":"public"},{"id":"18681","relation":"dissertation_contains","status":"public"},{"relation":"dissertation_contains","id":"12364","status":"public"}]},"day":"05"},{"month":"12","type":"journal_article","date_created":"2019-09-22T22:00:35Z","pmid":1,"volume":1724,"article_type":"original","department":[{"_id":"GaNo"}],"language":[{"iso":"eng"}],"scopus_import":"1","publisher":"Elsevier","publication_identifier":{"eissn":["1872-6240"],"issn":["0006-8993"]},"date_updated":"2025-07-10T11:54:01Z","title":"Modeling cell-cell interactions in the brain using cerebral organoids","day":"01","fulldoi":"https://doi.org/10.1016/j.brainres.2019.146458","isi":1,"oa_version":"None","date_published":"2019-12-01T00:00:00Z","author":[{"first_name":"Bárbara","full_name":"Oliveira, Bárbara","id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","last_name":"Oliveira"},{"first_name":"Aysan Çerağ","last_name":"Yahya","full_name":"Yahya, Aysan Çerağ","id":"365A65F8-F248-11E8-B48F-1D18A9856A87"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178","first_name":"Gaia"}],"publication_status":"published","abstract":[{"lang":"eng","text":"Until recently, a great amount of brain studies have been conducted in human post mortem tissues, cell lines and model organisms. These researches provided useful insights regarding cell-cell interactions occurring in the brain. However, such approaches suffer from technical limitations and inaccurate modeling of the tissue 3D cytoarchitecture. Importantly, they might lack a human genetic background essential for disease modeling. With the development of protocols to generate human cerebral organoids, we are now closer to reproducing the early stages of human brain development in vitro. As a result, more relevant cell-cell interaction studies can be conducted.\r\n\r\nIn this review, we discuss the advantages of 3D cultures over 2D in modulating brain cell-cell interactions during physiological and pathological development, as well as the progress made in developing organoids in which neurons, macroglia, microglia and vascularization are present. Finally, we debate the limitations of those models and possible future directions."}],"intvolume":"      1724","quality_controlled":"1","doi":"10.1016/j.brainres.2019.146458","year":"2019","_id":"6896","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","status":"public","citation":{"short":"B. Oliveira, A.Ç. Yahya, G. Novarino, Brain Research 1724 (2019).","mla":"Oliveira, Bárbara, et al. “Modeling Cell-Cell Interactions in the Brain Using Cerebral Organoids.” <i>Brain Research</i>, vol. 1724, 146458, Elsevier, 2019, doi:<a href=\"https://doi.org/10.1016/j.brainres.2019.146458\">10.1016/j.brainres.2019.146458</a>.","chicago":"Oliveira, Bárbara, Aysan Çerağ Yahya, and Gaia Novarino. “Modeling Cell-Cell Interactions in the Brain Using Cerebral Organoids.” <i>Brain Research</i>. Elsevier, 2019. <a href=\"https://doi.org/10.1016/j.brainres.2019.146458\">https://doi.org/10.1016/j.brainres.2019.146458</a>.","apa":"Oliveira, B., Yahya, A. Ç., &#38; Novarino, G. (2019). Modeling cell-cell interactions in the brain using cerebral organoids. <i>Brain Research</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.brainres.2019.146458\">https://doi.org/10.1016/j.brainres.2019.146458</a>","ista":"Oliveira B, Yahya AÇ, Novarino G. 2019. Modeling cell-cell interactions in the brain using cerebral organoids. Brain Research. 1724, 146458.","ieee":"B. Oliveira, A. Ç. Yahya, and G. Novarino, “Modeling cell-cell interactions in the brain using cerebral organoids,” <i>Brain Research</i>, vol. 1724. Elsevier, 2019.","ama":"Oliveira B, Yahya AÇ, Novarino G. Modeling cell-cell interactions in the brain using cerebral organoids. <i>Brain Research</i>. 2019;1724. doi:<a href=\"https://doi.org/10.1016/j.brainres.2019.146458\">10.1016/j.brainres.2019.146458</a>"},"article_processing_charge":"No","external_id":{"isi":["000491646600033"],"pmid":["31521639"]},"publication":"Brain Research","article_number":"146458"}]