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To better understand neuronal dysfunction during ALS progression, we studied motor neuron (MN) cultures derived from iPSC lines generated from <jats:italic>C9ORF72 (C9)<\/jats:italic> expansion carriers and unaffected controls. <jats:italic>C9<\/jats:italic> and control MN cultures showed comparable mRNA levels for MN markers <jats:italic>SMI-32, HB9<\/jats:italic> and <jats:italic>ISL1<\/jats:italic> and similar MN yields (&gt;\u200950% TUJ1\/SMI-32 double-positive MNs). Using whole-cell patch clamp we showed that <jats:italic>C9<\/jats:italic>-MNs have normal membrane capacitance, resistance and resting potential. However, immature (day 40) <jats:italic>C9<\/jats:italic>-MNs exhibited a hyperexcitable phenotype concurrent with increased release of calcium (Ca<jats:sup>2+<\/jats:sup>) from internal stores, but with no changes to Na<jats:sub>V<\/jats:sub> and K<jats:sub>V<\/jats:sub> currents. Interestingly, this was a transient phenotype. By day 47, maturing <jats:italic>C9<\/jats:italic>-MNs demonstrated normal electrophysiological activity, displaying only subtle alterations on\u00a0mitochondrial Ca<jats:sup>2+<\/jats:sup> release. Together, these findings suggest the potential importance of a developmental component to <jats:italic>C9ORF72<\/jats:italic>-related ALS.<\/jats:p>","DOI":"10.1038\/s41598-022-09751-3","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T18:04:11Z","timestamp":1651773851000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Hyperexcitability in young iPSC-derived C9ORF72 mutant motor neurons is associated with increased intracellular calcium release"],"prefix":"10.1038","volume":"12","author":[{"given":"Sarah","family":"Burley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayne A.","family":"Beccano-Kelly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Talbot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar Cordero","family":"Llana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Wade-Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"issue":"5\u20136","key":"9751_CR1","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3109\/17482960802566824","volume":"10","author":"A Chi\u00f2","year":"2009","unstructured":"Chi\u00f2, A. et al. 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