{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T23:38:39Z","timestamp":1789688319465,"version":"4.0.1"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,12]],"date-time":"2022-02-12T00:00:00Z","timestamp":1644624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1471\/17"],"award-info":[{"award-number":["1471\/17"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004375","name":"Tel Aviv University","doi-asserted-by":"publisher","award":["Leo Mintz"],"award-info":[{"award-number":["Leo Mintz"]}],"id":[{"id":"10.13039\/501100004375","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004375","name":"Tel Aviv University","doi-asserted-by":"publisher","award":["BrainBoost"],"award-info":[{"award-number":["BrainBoost"]}],"id":[{"id":"10.13039\/501100004375","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001735","name":"Weizmann Institute of Science","doi-asserted-by":"publisher","award":["The Azrieli Foundation and the Aufzien Family Center"],"award-info":[{"award-number":["The Azrieli Foundation and the Aufzien Family Center"]}],"id":[{"id":"10.13039\/501100001735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by a developmentally regulated silencing of the FMR1 gene, but its effect on human neuronal network development and function is not fully understood. Here, we isolated isogenic human embryonic stem cell (hESC) subclones\u2014one with a full FX mutation and one that is free of the mutation (control) but shares the same genetic background\u2014differentiated them into induced neurons (iNs) by forced expression of NEUROG-1, and compared the functional properties of the derived neuronal networks. High-throughput image analysis demonstrates that FX-iNs have significantly smaller cell bodies and reduced arborizations than the control. Both FX- and control-neurons can discharge repetitive action potentials, and FX neuronal networks are also able to generate spontaneous excitatory synaptic currents with slight differences from the control, demonstrating that iNs generate more mature neuronal networks than the previously used protocols. MEA analysis demonstrated that FX networks are hyperexcitable with significantly higher spontaneous burst-firing activity compared to the control. Most importantly, cross-correlation analysis enabled quantification of network connectivity to demonstrate that the FX neuronal networks are significantly less synchronous than the control, which can explain the origin of the development of intellectual dysfunction associated with FXS.<\/jats:p>","DOI":"10.3390\/ijms23042048","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T21:08:43Z","timestamp":1644786523000},"page":"2048","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Impaired Functional Connectivity Underlies Fragile X Syndrome"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-5568","authenticated-orcid":false,"given":"Lital","family":"Gildin","sequence":"first","affiliation":[{"name":"Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel"},{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8569-0810","authenticated-orcid":false,"given":"Rossana","family":"Rauti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-2577","authenticated-orcid":false,"given":"Ofir","family":"Vardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel"},{"name":"School of Electrical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liron","family":"Kuznitsov-Yanovsky","sequence":"additional","affiliation":[{"name":"Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel"},{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3823-7682","authenticated-orcid":false,"given":"Ben M.","family":"Maoz","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel"},{"name":"Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel"},{"name":"The Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7592-0408","authenticated-orcid":false,"given":"Menahem","family":"Segal","sequence":"additional","affiliation":[{"name":"Department of Brain Sciences, The Weizmann Institute, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalit","family":"Ben-Yosef","sequence":"additional","affiliation":[{"name":"Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel"},{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel"},{"name":"Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.neuron.2015.06.017","article-title":"Altered Neuronal and Circuit Excitability in Fragile X Syndrome","volume":"87","author":"Contractor","year":"2015","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41583-021-00432-0","article-title":"The molecular biology of FMRP: New insights into fragile X syndrome","volume":"22","author":"Richter","year":"2021","journal-title":"Nat. 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