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Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including<jats:italic>PRNP<\/jats:italic><jats:sup><jats:italic>E200K<\/jats:italic><\/jats:sup>, trisomy 21 (<jats:italic>T21)<\/jats:italic>, and<jats:italic>LRRK2<\/jats:italic><jats:sup>G2019S<\/jats:sup>, which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson\u2019s disease. We utilized no known disease\/healthy COs (<jats:italic>HC<\/jats:italic>) as normal function controls. At 3\u20134 and 6\u201310\u00a0months post-differentiation, COs with mutations showed no evidence of disease-related pathology. Electrophysiology assessment showed that all COs exhibited mature neuronal firing at 6\u201310\u00a0months old. At this age, we observed significant changes in the electrophysiology of the COs with disease-associated mutations (dCOs) as compared with the<jats:italic>HC<\/jats:italic>, including reduced neuronal network communication, slowing neuronal oscillations, and increased coupling of delta and theta phases to the amplitudes of gamma oscillations. Such changes were linked with the detection of hypersynchronous events like spike-and-wave discharges. These dysfunctions were associated with altered production and release of neurotransmitters, compromised activity of excitatory ionotropic receptors including receptors of kainate, AMPA, and NMDA, and changed levels and function of excitatory glutamatergic synapses and inhibitory GABAergic synapses. Neuronal properties that modulate GABAergic inhibition including the activity of Na\u2013K-Cl cotransport 1 (NKCC1) in Cl<jats:sup>\u2212<\/jats:sup>homeostasis and the levels of synaptic and extra-synaptic localization of GABA receptors (GABARs) were altered in the<jats:italic>T21<\/jats:italic>COs\u00a0only. The neurosteroid allopregnanolone, a positive modulator of GABARs, was downregulated in all the dCOs. Treatment with this neurosteroid significantly improved the neuronal communication in the dCOs, possibly through improving the GABAergic inhibition. Overall, without the manifestation of any disease-related pathology, the genetic mutations<jats:italic>PRNP<\/jats:italic><jats:sup><jats:italic>E200K<\/jats:italic><\/jats:sup>,<jats:italic>T21<\/jats:italic>, and<jats:italic>LRRK2<\/jats:italic><jats:sup>G2019S<\/jats:sup>significantly altered the neuronal network communication in dCOs by disrupting the excitatory-to-inhibitory balance.<\/jats:p>","DOI":"10.1186\/s13041-021-00864-w","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T12:06:04Z","timestamp":1633953964000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases"],"prefix":"10.1186","volume":"14","author":[{"given":"Simote T.","family":"Foliaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Schwarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley R.","family":"Groveman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan O.","family":"Walters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia C.","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina D.","family":"Orr\u00f9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia M.","family":"Schmit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe","family":"Freitag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenquan","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharine M.","family":"Bosio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7591-1149","authenticated-orcid":false,"given":"Cathryn L.","family":"Haigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,11]]},"reference":[{"issue":"7467","key":"864_CR1","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nature12517","volume":"501","author":"MA Lancaster","year":"2013","unstructured":"Lancaster MA, et al. 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