iPSC-derived homogeneous populations of developing schizophrenia cortical interneurons have compromised mitochondrial function

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Abstract

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs.

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  • 31 July 2019

    A correction to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

This study was supported by MH107884 (S.C.) and NYSTEM C32607GG (S.C.). We thank Karen F. Berman, MD and Jose Apud, MD PhD at the National Institute of Mental Health for their contribution in providing patient samples.

Authors contributions

P.N., H.N., G.-H.P., Z.S. and S.C. designed the experiments. P.N., H.N., G.-H.P., Z.S., Y.G., J.M.P., S.Y., J.S.P., J.T.C., C.Y., W.H. and S.C. conducted experiments, collected data, and analyzed the data. P.N., W.H., and S.C. wrote the manuscript. D.R.W., R.E.S., B.M.C. and D.L.M. provided patient cell lines and reviewed data interpretation and manuscript contents. H.-Y.K. performed statistical analysis. S.C. supported this study financially.

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Correspondence to Sangmi Chung.

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