Ni Peiyan, Noh Haneul, Park Gun-Hoo, Shao Zhicheng, Guan Youxin, Park James M, Yu Sophy, Park Joy S, Coyle Joseph T, Weinberger Daniel R, Straub Richard E, Cohen Bruce M, McPhie Donna L, Yin Changhong, Huang Weihua, Kim Hae-Young, Chung Sangmi
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.
Mol Psychiatry. 2020 Nov;25(11):2873-2888. doi: 10.1038/s41380-019-0423-3. Epub 2019 Apr 24.
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.
精神分裂症（SCZ）是一种神经发育障碍。因此，研究SCZ潜在的发病机制需要研究脑细胞的发育。在SCZ患者的尸检大脑中，始终观察到皮质中间神经元（cINs）存在异常。这些异常可能解释了SCZ患者γ振荡和认知功能的改变。值得注意的是，目前使用的抗精神病药物可改善精神病症状，但在逆转认知缺陷方面效果不佳。阐明SCZ发病机制，尤其是与认知缺陷相关的机制，可能会带来更好的治疗方法。我们从15个健康对照（HC）诱导多能干细胞（iPSC）系和15个SCZ iPSC系中生成了发育中的cINs同质群体。SCZ的cINs，而非SCZ谷氨酸能神经元，表现出氧化磷酸化（OxPhos）相关基因表达失调，并伴有线粒体功能受损。cINs中的OxPhos缺陷可被α硫辛酸/乙酰左旋肉碱（ALA/ALC）逆转，但不能被先前确定可增强线粒体功能的其他化学物质逆转。ALA/ALC恢复线粒体功能的同时，SCZ cINs的树突分支缺陷也得到了逆转。即使在没有任何与其他神经元亚型的回路环境的情况下，OxPhos异常似乎也是SCZ cINs的一种内在缺陷。
