31
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 ( CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.

          Related collections

          Most cited references76

          • Record: found
          • Abstract: found
          • Article: not found

          Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

          Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Rapid single-step induction of functional neurons from human pluripotent stem cells.

            Available methods for differentiating human embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs) into neurons are often cumbersome, slow, and variable. Alternatively, human fibroblasts can be directly converted into induced neuronal (iN) cells. However, with present techniques conversion is inefficient, synapse formation is limited, and only small amounts of neurons can be generated. Here, we show that human ESCs and iPSCs can be converted into functional iN cells with nearly 100% yield and purity in less than 2 weeks by forced expression of a single transcription factor. The resulting ES-iN or iPS-iN cells exhibit quantitatively reproducible properties independent of the cell line of origin, form mature pre- and postsynaptic specializations, and integrate into existing synaptic networks when transplanted into mouse brain. As illustrated by selected examples, our approach enables large-scale studies of human neurons for questions such as analyses of human diseases, examination of human-specific genes, and drug screening. Copyright © 2013 Elsevier Inc. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Model of autism: increased ratio of excitation/inhibition in key neural systems

                Bookmark

                Author and article information

                Contributors
                n.nadif@donders.ru.nl
                Journal
                Mol Psychiatry
                Mol Psychiatry
                Molecular Psychiatry
                Nature Publishing Group UK (London )
                1359-4184
                1476-5578
                10 May 2021
                10 May 2021
                2022
                : 27
                : 1
                : 1-18
                Affiliations
                [1 ]GRID grid.5590.9, ISNI 0000000122931605, Department of Human Genetics, , Radboudumc, Donders Institute for Brain, Cognition, and Behavior, ; Nijmegen, The Netherlands
                [2 ]GRID grid.5590.9, ISNI 0000000122931605, Department of Cognitive Neuroscience, , Radboudumc, Donders Institute for Brain, Cognition and Behavior, ; Nijmegen, The Netherlands
                [3 ]GRID grid.411760.5, ISNI 0000 0001 1378 7891, Division of Molecular Psychiatry, Center of Mental Health, , University Hospital Würzburg, ; Würzburg, Germany
                [4 ]GRID grid.448878.f, ISNI 0000 0001 2288 8774, Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, , I.M Sechenov First Moscow State Medical University, ; Moscow, Russia
                [5 ]GRID grid.5012.6, ISNI 0000 0001 0481 6099, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), , Maastricht University, ; Maastricht, The Netherlands
                [6 ]GRID grid.479666.c, ISNI 0000 0004 0409 5115, Department of Epileptology, , ACE Kempenhaeghe, ; Heeze, The Netherlands
                [7 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Centre for Molecular and Biomolecular Informatics, , Radboudumc, Radboud Institute for Molecular Life Sciences, ; Nijmegen, The Netherlands
                [8 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Centre for Developmental Neurobiology, , Institute of Psychiatry, Psychology and Neuroscience, King’s College London, ; London, UK
                [9 ]GRID grid.5590.9, ISNI 0000000122931605, Department of Anatomy, , Radboudumc, Donders Institute for Brain, Cognition, and Behavior, ; Nijmegen, The Netherlands
                [10 ]GRID grid.6214.1, ISNI 0000 0004 0399 8953, Department of Clinical Neurophysiology, , University of Twente, ; Enschede, The Netherlands
                Author information
                http://orcid.org/0000-0002-4393-5506
                http://orcid.org/0000-0001-8059-4109
                http://orcid.org/0000-0001-9572-3081
                http://orcid.org/0000-0002-3089-395X
                http://orcid.org/0000-0003-1952-6865
                http://orcid.org/0000-0001-8348-153X
                http://orcid.org/0000-0002-2153-9254
                http://orcid.org/0000-0002-1202-4363
                http://orcid.org/0000-0002-7448-9289
                Article
                1117
                10.1038/s41380-021-01117-x
                8960401
                33972691
                4cc5ed08-3e10-4786-aa1d-d02712b52748
                © 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
                : 7 May 2020
                : 30 March 2021
                : 13 April 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000893, Simons Foundation;
                Award ID: 610264
                Award Recipient :
                Funded by: ERA-NET NEURON DECODE! grant (NWO) 013.18.001 NWO-CAS grant 012.200.001 the Dutch epilepsiefonds WAR 18-02
                Funded by: the Netherlands Organization for Health Research and Development ZonMw grant 91217055
                Funded by: ERA-NET NEURON-102 SYNSCHIZ grant (NWO) 013-17-003 4538
                Funded by: Horizon 2020 (Eat2beNICE) grant 728018 (to K.P.L.); BMBF 01EW1902 (to K.P.L).
                Categories
                Article
                Custom metadata
                © The Author(s), under exclusive licence to Springer Nature Limited 2022

                Molecular medicine
                neuroscience,stem cells,cell biology
                Molecular medicine
                neuroscience, stem cells, cell biology

                Comments

                Comment on this article