학술논문
Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.
Document Type
Academic Journal
Author
Stern S; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel. sstern@univ.haifa.ac.il.; Zhang L; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.; Wang M; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.; Wright R; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.; Rosh I; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Hussein Y; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Stern T; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Choudhary A; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Tripathi U; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Reed P; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.; Sadis H; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Nayak R; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Shemen A; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Agarwal K; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Cordeiro D; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Peles D; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.; Hang Y; Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA, USA.; Mendes APD; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.; Baul TD; Department of Psychiatry at the Boston Medical Center, Boston, MA, USA.; Roth JG; Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Coorapati S; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.; Boks MP; Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.; McCombie WR; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.; Hulshoff Pol H; Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.; Department of Experimental Psychology, Utrecht University, Heidelberglaan 1, 3584CS, Utrecht, The Netherlands.; Brennand KJ; Nash Family Department of Neuroscience, Friedman Brain Institute, Pamela Sklar Division of Psychiatric Genomics, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.; Department of Psychiatry, Department of Genetics, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, 06511, USA.; Réthelyi JM; Molecular Psychiatry Research Group and Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.; Kahn RS; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research, Education and Clinical Center, James J Peters VA Medical Center, New York, NY, USA.; Marchetto MC; Department of Anthropology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.; Gage FH; Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA. gage@salk.edu.
Source
Publisher: Nature Publishing Group Specialist Journals Country of Publication: England NLM ID: 9607835 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5578 (Electronic) Linking ISSN: 13594184 NLM ISO Abbreviation: Mol Psychiatry Subsets: MEDLINE
Subject
Language
English
Abstract
Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.
(© 2024. The Author(s).)
(© 2024. The Author(s).)