Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Stern, S.; Zhang, L.; Wang, M.; Wright, R.; Cordeiro, D.; Peles, D.; Hang, Y.; Mendes, A. P.; Baul, T.; Roth, J.; Coorapati, S.; Boks, M.; Pol, H. H.; Brennand, K. J.; Rethelyi, J. M.; Kahn, R. S.; Marchetto, M. C.; Gage, F. H.

doi:10.1101/2022.05.13.491776

bioRxiv · 10.1101/2022.05.13.491776

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission

Stern, S.·Zhang, L.·Wang, M.·Wright, R.·Cordeiro, D.·Peles, D.·Hang, Y.·Mendes, A. P.·Baul, T.·Roth, J.·Coorapati, S.·Boks, M.·Pol, H. H.·Brennand, K. J.·Rethelyi, J. M.·Kahn, R. S.·Marchetto, M. C.·Gage, F. H.

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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. We characterized human-induced pluripotent stem cell (iPSC)-derived hippocampal neurons from two pairs of monozygotic twins that are discordant for a schizophrenia diagnosis. We compared the affected and the non-affected siblings and compared all of them to twin sets where none of the siblings suffered from schizophrenia. 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. The neurons in the unaffected co-twin group were also less arborized than the neurons from controls but more arborized than those from affected siblings. Some of their spike features were immature (but less immature than neurons derived from the affected siblings). Importantly, their synaptic activity was not affected. Since schizophrenia is a genetically complex disorder, our twin study allows the measurement of neuronal phenotypes with a similar genetic background. The differences between the siblings may arise due to changes that occurred after the split of the egg into twins. Therefore, our study confirms that dysregulation of synaptic pathways, as well as changes in the rate of synaptic events, distinguishes between individuals affected with schizophrenia and unaffected individuals, even in those having a very similar genetic background.

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Stern, S., Zhang, L., Wang, M., Wright, R., Cordeiro, D., Peles, D., Hang, Y., Mendes, A. P., Baul, T., Roth, J., Coorapati, S., Boks, M., Pol, H. H., Brennand, K. J., Rethelyi, J. M., Kahn, R. S., Marchetto, M. C., Gage, F. H.. 2022-05-13. Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission. https://doi.org/10.1101/2022.05.13.491776

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