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      Modeling psychiatric disorders: from genomic findings to cellular phenotypes

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          Abstract

          Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes.

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          Most cited references96

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          Abnormal neural oscillations and synchrony in schizophrenia.

          Converging evidence from electrophysiological, physiological and anatomical studies suggests that abnormalities in the synchronized oscillatory activity of neurons may have a central role in the pathophysiology of schizophrenia. Neural oscillations are a fundamental mechanism for the establishment of precise temporal relationships between neuronal responses that are in turn relevant for memory, perception and consciousness. In patients with schizophrenia, the synchronization of beta- and gamma-band activity is abnormal, suggesting a crucial role for dysfunctional oscillations in the generation of the cognitive deficits and other symptoms of the disorder. Dysfunctional oscillations may arise owing to anomalies in the brain's rhythm-generating networks of GABA (gamma-aminobutyric acid) interneurons and in cortico-cortical connections.
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            A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.

            Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. Copyright © 2010 Elsevier Inc. All rights reserved.
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              A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein.

              Recently, several groups have developed green fluorescent protein (GFP)-based Ca(2+) probes. When applied in cells, however, these probes are difficult to use because of a low signal-to-noise ratio. Here we report the development of a high-affinity Ca(2+) probe composed of a single GFP (named G-CaMP). G-CaMP showed an apparent K(d) for Ca(2+) of 235 nM. Association kinetics of Ca(2+) binding were faster at higher Ca(2+) concentrations, with time constants decreasing from 230 ms at 0.2 microM Ca(2+) to 2.5 ms at 1 microM Ca(2+). Dissociation kinetics (tau approximately 200 ms) are independent of Ca(2+) concentrations. In HEK-293 cells and mouse myotubes expressing G-CaMP, large fluorescent changes were observed in response to application of drugs or electrical stimulations. G-CaMP will be a useful tool for visualizing intracellular Ca2+ in living cells. Mutational analysis, together with previous structural information, suggests the residues that may alter the fluorescence of GFP.
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                Author and article information

                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                September 2016
                31 May 2016
                : 21
                : 9
                : 1167-1179
                Affiliations
                [1 ]Department of Neuroscience, Karolinska Institutet , Stockholm, Sweden
                [2 ]Department of Pediatrics/Child Neurology, VU University Medical Center Amsterdam , Amsterdam, The Netherlands
                [3 ]Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam , Amsterdam, The Netherlands
                [4 ]Neuroscience and Mental Health Research Institute & School of Biosciences, Cardiff University , Cardiff, UK
                [5 ]Department of Genetics, University of North Carolina , Chapel Hill, NC, USA
                [6 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , Stockholm, Sweden
                [7 ]Department of Psychiatry, University of North Carolina , Chapel Hill, NC, USA
                [8 ]Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn and German Center for Neurodegenerative Diseases (DZNE) , Bonn, Germany
                [9 ]Regenerative Medicine Institute, School of Medicine , NUI Galway, Galway, Ireland
                [10 ]Department of Biology, Faculty of Medicine, Masaryk University , Brno, Czech Republic
                [11 ]Department of Molecular Medicine, University of Oslo, and Norwegian Center for Stem Cell Research, Oslo University Hospital , Oslo, Norway
                [12 ]Department Clinical Genetics, Vrije Universiteit Medical Center, Neuroscience Campus Amsterdam , Amsterdam, The Netherlands
                [13 ]Department of Medical Genetics, Oslo University Hospital, University of Bergen , Oslo, Norway
                [14 ]NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen , Bergen, Norway
                Author notes
                [* ]Department of Medical Genetics, Oslo University Hospital, University of Bergen , Kirkeveien 166, PO Box 4956 Nydalen, Oslo 0424, Norway. E-mail: srdjan.djurovic@ 123456medisin.uio.no
                Article
                mp201689
                10.1038/mp.2016.89
                4995546
                27240529
                1489b07b-688e-4bf6-9dec-5d02320b5537
                Copyright © 2016 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 25 November 2015
                : 20 April 2016
                : 21 April 2016
                Categories
                Expert Review

                Molecular medicine
                Molecular medicine

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