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We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the<jats:italic>MAPT<\/jats:italic>10+16 splice-site mutation. This mutation leads to the increased splicing of 4R tau isoforms. However, the role of different isoforms of tau protein in initiating neuronal dementia-related dysfunction, and the causality between the<jats:italic>MAPT<\/jats:italic>10+16 mutation and altered neuronal activity have remained unclear. Here, we employed genetically engineered cells, in which the IVS10+16 mutation was introduced into healthy donor iPSCs to increase the expression of 4R tau isoform in exon 10, aiming to explore key physiological traits of iPSC-derived<jats:italic>MAPT<\/jats:italic>IVS10+16 neurons using patch-clamp electrophysiology and multiphoton fluorescent imaging techniques. We found that during late in vitro neurogenesis (from ~180 to 230 days) iPSC-derived cortical neurons of the control group (parental wild-type tau) exhibited membrane properties compatible with \u201cmature\u201d neurons. In contrast,<jats:italic>MAPT<\/jats:italic>IVS10+16 neurons displayed impaired excitability, as reflected by a depolarized resting membrane potential, an increased input resistance, and reduced voltage-gated Na<jats:sup>+<\/jats:sup>- and K<jats:sup>+<\/jats:sup>-channel-mediated currents. The mutation changed the channel properties of fast-inactivating Na<jats:sub>v<\/jats:sub>and decreased the Na<jats:sub>v<\/jats:sub>1.6 protein level.<jats:italic>MAPT<\/jats:italic>IVS10+16 neurons exhibited reduced firing accompanied by a changed action potential waveform and severely disturbed intracellular Ca<jats:sup>2+<\/jats:sup>dynamics, both in the soma and dendrites, upon neuronal depolarization. These results unveil a causal link between the<jats:italic>MAPT<\/jats:italic>10+16 mutation, hence overproduction of 4R tau, and a dysfunction of human cells, identifying a biophysical basis of changed neuronal activity in 4R tau-triggered dementia. Our study lends further support to using iPSC lines as a suitable platform for modelling tau-induced human neuropathology in vitro.<\/jats:p>","DOI":"10.1038\/s41419-021-04007-w","type":"journal-article","created":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T11:03:00Z","timestamp":1626519780000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3921-3674","authenticated-orcid":false,"given":"Olga","family":"Kopach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7938-6131","authenticated-orcid":false,"given":"Noem\u00ed","family":"Esteras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3062-7050","authenticated-orcid":false,"given":"Selina","family":"Wray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey Y.","family":"Abramov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9539-9947","authenticated-orcid":false,"given":"Dmitri A.","family":"Rusakov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,17]]},"reference":[{"key":"4007_CR1","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/0896-6273(89)90210-9","volume":"3","author":"M Goedert","year":"1989","unstructured":"Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. 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