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To date, the mechanism by which <jats:italic>SETD5<\/jats:italic> haploinsufficiency causes ASD\/ID remains an unanswered question. <jats:italic>Setd5<\/jats:italic> is the highly conserved mouse homolog, and although the <jats:italic>Setd5<\/jats:italic> null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. <jats:italic>Setd5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal <jats:italic>Setd5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> cortical neurons showed altered gene expression of neurodevelopment-related genes. <jats:italic>Setd5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in <jats:italic>Setd5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by <jats:italic>Setd5<\/jats:italic> haploinsufficiency, consistent with a highly penetrant risk factor.<\/jats:p>","DOI":"10.1038\/s41398-018-0344-y","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T17:03:43Z","timestamp":1547744623000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9811-9007","authenticated-orcid":false,"given":"Spencer M.","family":"Moore","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason S.","family":"Seidman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1504-3321","authenticated-orcid":false,"given":"Jacob","family":"Ellegood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Savchenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ty D.","family":"Troutman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Stender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daehoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sicong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Voytek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason P.","family":"Lerch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4227-2982","authenticated-orcid":false,"given":"Hoonkyo","family":"Suh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher K","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0867-2875","authenticated-orcid":false,"given":"Alysson R.","family":"Muotri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,1,17]]},"reference":[{"key":"344_CR1","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1016\/j.cell.2012.06.048","volume":"150","author":"I Pinheiro","year":"2012","unstructured":"Pinheiro, I. et al. 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