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Despite extensive previous studies in adult animal models, a possible embryonic root of this syndrome has not been determined. Here, in neurons from a 22q11.2 DS mouse model (\n                    <jats:italic>Lgdel<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ), we found embryonic-premature alterations in the neuronal chloride cotransporters indicated by dysregulated NKCC1 and KCC2 protein expression levels. We demonstrate with large-scale spiking activity recordings a concurrent deregulation of the spontaneous network activity and homeostatic network plasticity. Additionally,\n                    <jats:italic>Lgdel<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    networks at early development show abnormal neuritogenesis and void of synchronized spontaneous activity. Furthermore, parallel experiments on\n                    <jats:italic>Dgcr8<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mouse cultures reveal a significant, yet not exclusive contribution of the\n                    <jats:italic>dgcr8<\/jats:italic>\n                    gene to our phenotypes of\n                    <jats:italic>Lgdel<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    networks. Finally, we show that application of bumetanide, an inhibitor of NKCC1, significantly decreases the hyper-excitable action of GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor signaling and restores network homeostatic plasticity in\n                    <jats:italic>Lgdel<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    networks. Overall, by exploiting an on-a-chip 22q11.2 DS model, our results suggest a delayed GABA-switch in\n                    <jats:italic>Lgdel<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    neurons, which may contribute to a delayed embryonic development. Prospectively, acting on the GABA-polarity switch offers a potential target for 22q11.2 DS therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-15793-9","type":"journal-article","created":{"date-parts":[[2017,11,10]],"date-time":"2017-11-10T10:58:10Z","timestamp":1510311490000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Developmental excitatory-to-inhibitory GABA-polarity switch is disrupted in 22q11.2 deletion syndrome: a potential target for clinical therapeutics"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6515-2991","authenticated-orcid":false,"given":"Hayder","family":"Amin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6609-1134","authenticated-orcid":false,"given":"Federica","family":"Marinaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9537-8900","authenticated-orcid":false,"given":"Davide","family":"De Pietri Tonelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9521-2812","authenticated-orcid":false,"given":"Luca","family":"Berdondini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,16]]},"reference":[{"key":"15793_CR1","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.ijdevneu.2010.09.007","volume":"29","author":"LJ Drew","year":"2011","unstructured":"Drew, L. 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