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

With the aim of modeling Cortical interneurons -intrinsic SCZ pathogenetic mechanisms without the presence of other neuronal subtypes, we developed an efficient method of generating a homogeneous population of medial ganglionic eminence -derived developmental cINs from human pluripotent stem cells, as described in our previous studies27, 28

Peiyan Ni; Haneul Noh; Gun-Hoo Park; Zhicheng Shao; Youxin Guan; James M. Park; Sophy Yu; Joy S. Park; Joseph T. Coyle; Daniel R. Weinberger; Richard E. Straub; Bruce M. Cohen; Donna L. McPhie; Changhong Yin; Weihua Huang; Hae-Young Kim; Sangmi Chung

2019

Scholarcy highlights

  • Schizophrenia is a debilitating neurodevelopmental disorder with pathogenetic roots during development, much before the most prominent symptoms of psychosis appear in adolescence
  • Homogeneous populations of developmental Cortical interneurons were generated from healthy control vs. SCZ iPSCs
  • As the first step in studying SCZ pathogenetic mechanisms in disease-relevant developmental tissues, we generated iPSCs from 9 HC vs. 9 SCZ fibroblast lines using modified RNA methods
  • All reprogrammed iPSCs showed human pluripotent stem cells-like morphology and expressed hPSC markers
  • A significant deficit was observed in reserve capacity and maximal respiration without a significant change in basal respiration in SCZ cINs, suggesting that SCZ cINs may not respond to stressful environments as effectively as HC cINs
  • One drop of DMEM with Glutamax with 10% fetal bovine serum, 2% L-Glutamine, 1% Penicillin/Streptomycin solution, and 1% Amphotericin and Gentamicin solution was added on each piece of skin and put in an incubator
  • Due to side effects of antipsychotics on mitochondrial function, it has not been clear whether the OxPhos deficits observed in postmortem SCZ brains were SCZ-innate abnormalities or the side effect of drug treatment
  • These observations were not a result of antipsychotic treatment and were confirmed in the absence of other neuronal subtypes that can affect the functionality of Cortical interneurons, revealing what is inherent to these SCZ cINs. The OxPhox abnormalities in these cINs could be reversed by one of the chemical treatments reported to enhance mitochondrial function, accompanied by restoration of other downstream abnormalities, abnormal arborization

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