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No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell\u2010derived technologies, including human neurons,\n                    <jats:italic>MECP2<\/jats:italic>\n                    \u2010mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of\n                    <jats:italic>MECP2<\/jats:italic>\n                    and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed\n                    <jats:italic>MECP2\u2010<\/jats:italic>\n                    knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202012523","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T05:15:48Z","timestamp":1607404548000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Pharmacological reversal of synaptic and network pathology in human MECP2\u2010KO neurons and cortical organoids"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0675-6437","authenticated-orcid":false,"given":"Cleber A","family":"Trujillo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason W","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla D","family":"Negraes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassiano","family":"Carromeu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Tejwani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan","family":"Acab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Tsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Sodhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M","family":"Fichter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Zanella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terrence J","family":"Sejnowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Ulrich","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":[[2020,12,8]]},"reference":[{"key":"BFEMMM202012523_CR1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1152\/physiol.00005.2019","volume":"34","author":"JW Adams","year":"2019","unstructured":"Adams JW, Cugola FR, Muotri AR (2019) Brain organoids as tools for modeling human neurodevelopmental disorders. 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