TY - JOUR
T1 - Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission
AU - Stern, Shani
AU - Zhang, Lei
AU - Wang, Meiyan
AU - Wright, Rebecca
AU - Rosh, Idan
AU - Hussein, Yara
AU - Stern, Tchelet
AU - Choudhary, Ashwani
AU - Tripathi, Utkarsh
AU - Reed, Patrick
AU - Sadis, Hagit
AU - Nayak, Ritu
AU - Shemen, Aviram
AU - Agarwal, Karishma
AU - Cordeiro, Diogo
AU - Peles, David
AU - Hang, Yuqing
AU - Mendes, Ana P.D.
AU - Baul, Tithi D.
AU - Roth, Julien G.
AU - Coorapati, Shashank
AU - Boks, Marco P.
AU - McCombie, W. Richard
AU - Hulshoff Pol, Hilleke
AU - Brennand, Kristen J.
AU - Réthelyi, János M.
AU - Kahn, René S.
AU - Marchetto, Maria C.
AU - Gage, Fred H.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/10
Y1 - 2024/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85192082331&partnerID=8YFLogxK
U2 - 10.1038/s41380-024-02561-1
DO - 10.1038/s41380-024-02561-1
M3 - Article
C2 - 38704507
AN - SCOPUS:85192082331
SN - 1359-4184
VL - 29
SP - 3208
EP - 3222
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 10
ER -