Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, B Rappaport Faculty of Medicine and B Rappaport Research Institute, Technion, Haifa, Israel.
Mol Psychiatry. 2013 Oct;18(10):1067-76. doi: 10.1038/mp.2013.67. Epub 2013 Jun 4.
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.
有一种流行的假说认为精神分裂症是一种神经发育障碍，涉及多巴胺能和谷氨酸能系统的功能障碍。越来越多的证据表明线粒体是精神分裂症的另一个病理因素。一种有吸引力的研究精神分裂症相关神经发育过程的模型是将体细胞重编程为诱导多能干细胞（iPSC），并将其分化为不同的神经元谱系。从三名精神分裂症患者和两名对照者的毛囊角质形成细胞中重编程了 iPSC，因为它们易于获取且与神经元具有共同的外胚层起源。iPSC 分化为 Pax6(+) / Nestin(+) 神经前体细胞，然后进一步分化为 β3-Tubulin(+) /酪氨酸羟化酶(+) / DAT(+)多巴胺能神经元。此外，iPSC 通过胚胎体分化为 β3-Tubulin(+) / Tbox brain1(+) 谷氨酸能神经元。精神分裂症衍生的多巴胺能细胞显示出严重受损的分化能力，而谷氨酸能细胞则无法成熟。精神分裂症衍生的角质形成细胞和 iPSC 的线粒体呼吸及其对多巴胺诱导抑制的敏感性受损。此外，我们观察到在多巴胺能神经元分化过程中和谷氨酸能细胞中，线粒体膜电位（Δψm）耗散以及线粒体网络结构和连接性的扰动。我们的数据揭示了神经分化和线粒体功能的紊乱，这可能是相互关联的，与精神分裂症中神经发育过程的功能障碍有关。
