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Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3\u03b2 inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper-to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3\u03b2, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11.2 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.<\/jats:p>","DOI":"10.1101\/2024.03.29.587339","type":"posted-content","created":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T22:20:12Z","timestamp":1711923612000},"source":"Crossref","is-referenced-by-count":4,"title":["Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5669-4369","authenticated-orcid":false,"given":"F.G.","family":"Alvino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2757-3306","authenticated-orcid":false,"given":"S.","family":"Gini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2308-6330","authenticated-orcid":false,"given":"A.","family":"Minetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6052-6931","authenticated-orcid":false,"given":"M.","family":"Pagani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5901-6144","authenticated-orcid":false,"given":"D.","family":"Sastre-Yag\u00fce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6399-436X","authenticated-orcid":false,"given":"N.","family":"Barsotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6675-4014","authenticated-orcid":false,"given":"E.","family":"De Guzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8411-0968","authenticated-orcid":false,"given":"C.","family":"Schleifer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1630-6066","authenticated-orcid":false,"given":"A.","family":"Stuefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2650-7147","authenticated-orcid":false,"given":"L.","family":"Kushan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-0302","authenticated-orcid":false,"given":"C.","family":"Montani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7213-0013","authenticated-orcid":false,"given":"A.","family":"Galbusera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6326-0657","authenticated-orcid":false,"given":"F.","family":"Papaleo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6780-8619","authenticated-orcid":false,"given":"M. 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