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Abstract：
Schizophrenia is a major psychiatric disorder, but the molecular mechanisms leading to its initiation or progression remain unclear. To elucidate the pathophysiology of schizophrenia, we used an in vitro neuronal cell culture model involving human induced pluripotent stem cells (hiPSCs) derived from a monozygotic-twin discordant schizophrenia pair. The cultured neurons differentiated from hiPSCs were composed of a mixture of glutamatergic excitatory neurons and gamma aminobutyric acid (GABA)ergic inhibitory neurons. In the electrophysiological analysis, a different pattern of spontaneous neuronal activity was observed under the condition without any stimulants. The frequency of spontaneous excitatory post-synaptic currents (sEPSCs) was significantly higher in the hiPSC-derived neurons of the patient with schizophrenia than in the control sibling at day-in-vitro 30. However, the synaptic formation was not different between the patient with schizophrenia and the control sibling during the same culture period. To explain underlying mechanisms of higher excitability of presynaptic cells, we focused on the potassium-chloride co-transporter KCC2, which contributes to excitatory-to-inhibitory GABA polarity switch in developing neurons. We also revealed the altered expression pattern of KCC2 in hiPSC-derived neurons from the patient with schizophrenia, which could contribute to understanding the pathology of schizophrenia in the developing nervous system.
摘要：
精神分裂症是一种主要的精神疾病，但导致其启动或进展的分子机制尚不清楚.为了阐明精神分裂症的病理生理学，我们使用了一种体外神经元细胞培养模型,该模型涉及来自单卵-双卵不一致精神分裂症对的人诱导多能干细胞(hiPSCs).从hiPSC分化的培养的神经元由谷氨酸能兴奋性神经元和γ氨基丁酸(GABA)能抑制神经元的混合物组成。在电生理学分析中，在没有任何刺激物的条件下观察到不同的自发神经元活动模式。在第30天，精神分裂症患者的hiPSC衍生的神经元中自发兴奋性突触后电流（sEPSC）的频率明显高于对照同胞。然而,在同一培养期间，精神分裂症患者和对照同胞之间的突触形成没有差异。为了解释突触前细胞高兴奋性的潜在机制，我们重点研究了氯化钾协同转运蛋白KCC2，它有助于发育中的神经元中兴奋性至抑制性GABA极性转换。我们还揭示了来自精神分裂症患者的hiPSC来源的神经元中KCC2的表达模式的改变，这可能有助于理解精神分裂症在神经系统发育中的病理学。
