Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Shani Stern, Lei Zhang, Meiyan Wang, Rebecca Wright, Idan Rosh, Yara Hussein, Tchelet Stern, Ashwani Choudhary, Utkarsh Tripathi, Patrick Reed, Hagit Sadis, Ritu Nayak, Aviram Shemen, Karishma Agarwal, Diogo Cordeiro, David Peles, Yuqing Hang, Ana P.D. Mendes, Tithi D. Baul, Julien G. RothShashank Coorapati, Marco P. Boks, W. Richard McCombie, Hilleke Hulshoff Pol, Kristen J. Brennand, János M. Réthelyi, René S. Kahn, Maria C. Marchetto, Fred H. Gage

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalMolecular Psychiatry
Early online date4 May 2024
DOIs
StateE-pub ahead of print - 4 May 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology

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