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Human-based test systems that allow studies on glutamate signalling are still scarce. To address this issue, we developed and characterized pluripotent stem cell (PSC)-based neural cultures capable of forming a functional network. Starting from a stably proliferating neuroepithelial stem cell (NESC) population, we generate \u201cmixed cortical cultures\u201d (MCC) within 24\u00a0days. Characterization by immunocytochemistry, gene expression profiling and functional tests (multi-electrode arrays) showed that MCC contain various functional neurotransmitter receptors, and in particular, the <jats:italic>N<\/jats:italic>-methyl-<jats:sc>d<\/jats:sc>-aspartate subtype of ionotropic glutamate receptors (NMDA-R). As this important receptor is found neither on conventional neural cell lines nor on most stem cell-derived neurons, we focused here on the characterization of rapid glutamate-triggered Ca<jats:sup>2+<\/jats:sup> signalling. Changes of the intracellular free calcium ion concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) were measured by fluorescent imaging as the main endpoint, and a method to evaluate and quantify signals in hundreds of cells at the same time was developed. We observed responses to glutamate in the low \u00b5M range. MCC responded to kainate and \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and a subpopulation of 50% had functional NMDA-R. The receptor was modulated by Mg<jats:sup>2+<\/jats:sup>, Zn<jats:sup>2+<\/jats:sup> and Pb<jats:sup>2+<\/jats:sup> in the expected ways, and various toxicologically relevant agonists (quinolinic acid, ibotenic acid, domoic acid) triggered [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> responses in MCC. Antagonists, such as phencyclidine, ketamine and dextromethorphan, were also readily identified. Thus, the MCC developed here may fill an important gap in the panel of test systems available to characterize the effects of chemicals on neurotransmitter receptors.<\/jats:p>","DOI":"10.1007\/s00204-021-03024-0","type":"journal-article","created":{"date-parts":[[2021,3,13]],"date-time":"2021-03-13T06:02:32Z","timestamp":1615615352000},"page":"1703-1722","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A human stem cell-derived test system for agents modifying neuronal N-methyl-d-aspartate-type glutamate receptor Ca2+-signalling"],"prefix":"10.1007","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9291-6862","authenticated-orcid":false,"given":"Stefanie","family":"Klima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Br\u00fcll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Sophie","family":"Spreng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilinca","family":"Suciu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjalda","family":"Falt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens C.","family":"Schwamborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Waldmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiaan","family":"Karreman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Leist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,13]]},"reference":[{"issue":"4","key":"3024_CR1","doi-asserted-by":"publisher","first-page":"441","DOI":"10.14573\/altex.1406111","volume":"31","author":"N Al\u00e9p\u00e9e","year":"2014","unstructured":"Al\u00e9p\u00e9e N, Bahinski A, Daneshian M et al (2014) State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology. 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