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The neuropathology of HD is characterized by the decline of a specific neuronal population within the brain, the striatal medium spiny neurons (MSNs). The origins of this extreme vulnerability remain unknown. Human induced pluripotent stem cell (hiPS cell)-derived MSNs represent a powerful tool to study this genetic disease. However, the differentiation protocols published so far show a high heterogeneity of neuronal populations in vitro. Here, we compared two previously published protocols to obtain hiPS cell-derived striatal neurons from both healthy donors and HD patients. Patch-clamp experiments, immunostaining and RT-qPCR were performed to characterize the neurons in culture. While the neurons were mature enough to fire action potentials, a majority failed to express markers typical for MSNs. Voltage-clamp experiments on voltage-gated sodium (Nav) channels revealed a large variability between the two differentiation protocols. Action potential analysis did not reveal changes induced by the HD mutation. This study attempts to demonstrate the current challenges in reproducing data of previously published differentiation protocols and in generating hiPS cell-derived striatal MSNs to model a genetic neurodegenerative disorder in vitro.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-85656-x","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T07:06:58Z","timestamp":1616656018000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The difficulty to model Huntington\u2019s disease in vitro using striatal medium spiny neurons differentiated from human induced pluripotent stem cells"],"prefix":"10.1038","volume":"11","author":[{"given":"Kim","family":"Le Cann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Foerster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"R\u00f6sseler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andelain","family":"Erickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Hautvast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Giesselmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Pensold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Kurth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Rothermel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia B.","family":"Mattis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine","family":"Zimmer-Bensch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"von H\u00f6rsten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Denecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Clarner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannis","family":"Meents","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Lampert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"85656_CR1","doi-asserted-by":"publisher","first-page":"267","DOI":"10.2217\/nmt.13.18","volume":"3","author":"OW Quarrell","year":"2013","unstructured":"Quarrell, O. W. et al. Managing juvenile Huntington\u2019s disease. Neurodegener. Dis. Manag. 3, 267\u2013276 (2013).","journal-title":"Neurodegener. Dis. Manag."},{"key":"85656_CR2","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","volume":"89","author":"F Saudou","year":"2016","unstructured":"Saudou, F. & Humbert, S. The biology of Huntingtin. Neuron 89, 910\u2013926 (2016).","journal-title":"Neuron"},{"key":"85656_CR3","doi-asserted-by":"publisher","first-page":"112","DOI":"10.5214\/ans.0972.7531.210308","volume":"21","author":"AA Rikani","year":"2014","unstructured":"Rikani, A. A. et al. The mechanism of degeneration of striatal neuronal subtypes in Huntington disease. Ann. Neurosci. 21, 112\u2013114 (2014).","journal-title":"Ann. Neurosci."},{"key":"85656_CR4","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.stem.2012.04.027","volume":"11","author":"VB Mattis","year":"2012","unstructured":"Mattis, V. B. et al. Induced pluripotent stem cells from patients with Huntington\u2019s disease show CAG repeat expansion associated phenotypes. Cell Stem Cell 11, 264\u2013278 (2012).","journal-title":"Cell Stem Cell"},{"key":"85656_CR5","doi-asserted-by":"crossref","unstructured":"Menalled, L. et al. Systematic behavioral evaluation of Huntington\u2019s disease transgenic and knock-in mouse models. Neurobiol Dis. 35, 319\u2013336 (2010).","DOI":"10.1016\/j.nbd.2009.05.007"},{"key":"85656_CR6","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.nbd.2015.10.016","volume":"86","author":"AB Rocher","year":"2016","unstructured":"Rocher, A. B. et al. Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington\u2019s disease. Neurobiol. Dis. 86, 131\u2013139 (2016).","journal-title":"Neurobiol. 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