Abstract
One of the prevailing hypotheses suggests schizophrenia as a neurodevelopmental disorder, involving dysfunction of dopaminergic and glutamatergic systems. Accumulating evidence suggests mitochondria as an additional pathological factor in schizophrenia. An attractive model to study processes related to neurodevelopment in schizophrenia is reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and differentiating them into different neuronal lineages. iPSCs from three schizophrenia patients and from two controls were reprogrammed from hair follicle keratinocytes, because of their accessibility and common ectodermal origin with neurons. iPSCs were differentiated into Pax6+/Nestin+ neural precursors and then further differentiated into β3-Tubulin+/tyrosine hydroxylase+/DAT+ dopaminergic neurons. In addition, iPSCs were differentiated through embryonic bodies into β3-Tubulin+/Tbox brain1+ glutamatergic neurons. Schizophrenia-derived dopaminergic cells showed severely impaired ability to differentiate, whereas glutamatergic cells were unable to maturate. Mitochondrial respiration and its sensitivity to dopamine-induced inhibition were impaired in schizophrenia-derived keratinocytes and iPSCs. Moreover, we observed dissipation of mitochondrial membrane potential (Δψm) and perturbations in mitochondrial network structure and connectivity in dopaminergic along the differentiation process and in glutamatergic cells. Our data unravel perturbations in neural differentiation and mitochondrial function, which may be interconnected, and of relevance to dysfunctional neurodevelopmental processes in schizophrenia.
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Acknowledgements
This study was supported by grants from the National Alliance for Research on Schizophrenia and Affective Disorders NARSAD, Chief Scientist of the Israeli Ministry of Health and Israel Science Foundation (grant no. 2016809). FJ Müller is supported by the Else Kröner-Fresenius-Stiftung fellowship. We thank G Mostoslavsky (Boston University School of Medicine) for providing the STEMCCA vector, E Suss-Toby for assistance in confocal microscopy experiments, A Greenberg and N Levy for assistance in HPLC studies and I Laevsky for the karyotyping.
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Robicsek, O., Karry, R., Petit, I. et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry 18, 1067–1076 (2013). https://doi.org/10.1038/mp.2013.67
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DOI: https://doi.org/10.1038/mp.2013.67
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