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      Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function

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          Abstract

          Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. 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–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) 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 (<1 mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (>1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABA A-receptor antagonist. Patch–clamp 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.

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          Induction of pluripotent stem cells from adult human fibroblasts by defined factors.

          Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.
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            Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks.

            Efficient derivation of human cerebral neocortical neural stem cells (NSCs) and functional neurons from pluripotent stem cells (PSCs) facilitates functional studies of human cerebral cortex development, disease modeling and drug discovery. Here we provide a detailed protocol for directing the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) to all classes of cortical projection neurons. We demonstrate an 80-d, three-stage process that recapitulates cortical development, in which human PSCs (hPSCs) first differentiate to cortical stem and progenitor cells that then generate cortical projection neurons in a stereotypical temporal order before maturing to actively fire action potentials, undergo synaptogenesis and form neural circuits in vitro. Methods to characterize cortical neuron identity and synapse formation are described.
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              Bioresorbable Silicon Electronics for Transient Spatio-temporal Mapping of Electrical Activity from the Cerebral Cortex

              Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include post-operative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, that record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required.
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                Author and article information

                Contributors
                sebastian.illes@gu.se
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                12 May 2021
                12 May 2021
                2021
                : 11
                : 281
                Affiliations
                [1 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Institute of Neuroscience and Physiology, , Sahlgrenska Academy at University of Gothenburg, ; Gothenburg, Sweden
                [2 ]GRID grid.411327.2, ISNI 0000 0001 2176 9917, Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, , Heinrich Heine University, ; Düsseldorf, Germany
                [3 ]Result Medical GmbH, Düsseldorf, Germany
                [4 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, , Sahlgrenska Academy at University of Gothenburg, ; Gothenburg, Sweden
                [5 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Sahlgrenska Cancer Center, Institute of Biomedicine, , Sahlgrenska Academy at University of Gothenburg, ; Gothenburg, Sweden
                [6 ]GRID grid.1649.a, ISNI 000000009445082X, Oncology Laboratory, Department of Pathology, , Sahlgrenska University Hospital, ; Gothenburg, Sweden
                [7 ]GRID grid.21604.31, ISNI 0000 0004 0523 5263, Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, , Paracelsus Medical University, ; Salzburg, Austria
                Author information
                http://orcid.org/0000-0003-4990-3545
                http://orcid.org/0000-0002-5881-6067
                http://orcid.org/0000-0002-2328-5382
                Article
                1399
                10.1038/s41398-021-01399-3
                8115174
                33980815
                2e015e7e-0668-49fd-8ff2-fe0a68085f9b
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 August 2020
                : 10 April 2021
                : 19 April 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100008599, Alzheimerfonden;
                Award ID: AF-556051, AF-744871
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003769, Eisai;
                Funded by: FundRef https://doi.org/10.13039/501100003186, Fredrik och Ingrid Thurings Stiftelse (Fredrik and Ingrid Thurings Foundation);
                Award ID: 2016-00225
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100006285, Magnus Bergvalls Stiftelse (Magnus Bergvall Foundation);
                Award ID: 2019-03512
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Clinical Psychology & Psychiatry
                stem cells,molecular neuroscience
                Clinical Psychology & Psychiatry
                stem cells, molecular neuroscience

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