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Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch\u2013clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (&lt;1\u2009mM) and overdose concentrations (&gt;1\u2009mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (&lt;1\u2009mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (&gt;1\u2009mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABA<jats:sub>A<\/jats:sub>-receptor antagonist. Patch\u2013clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.<\/jats:p>","DOI":"10.1038\/s41398-021-01399-3","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T04:04:20Z","timestamp":1620792260000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4990-3545","authenticated-orcid":false,"given":"Julia","family":"Izsak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Seth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Iljin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5881-6067","authenticated-orcid":false,"given":"Stephan","family":"Theiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"\u00c5gren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Funa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwig","family":"Aigner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Hanse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2328-5382","authenticated-orcid":false,"given":"Sebastian","family":"Illes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"1399_CR1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1111\/j.1399-5618.2009.00714.x","volume":"11","author":"R Machado-Vieira","year":"2009","unstructured":"Machado-Vieira, R., Manji, H. 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EISAI was not involved or influencing study design, data acquisition, and interpretation. S.I. holds a position at the company Cellectricon. Cellectricon was not involved in the study, and all experiments and data analysis were conducted at the Sahlgrenska Academy at the University of Gothenburg. S.T. is founder of the company Result Medical GmbH, D\u00fcsseldorf, Germany. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"281"}}