Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

精神分裂症影响着大约 1% 的世界人口。众所周知，遗传学、表观遗传学和环境因素在这种精神疾病中发挥着作用。虽然同卵双胞胎的一致性很高，但大约一半的双胞胎在精神分裂症方面不一致。为了解决同卵双胞胎中的一致性如何以及何时发生的问题，我们从两对精神分裂症不一致的双胞胎（其中一个兄弟姐妹患有精神分裂症，而第二个兄弟姐妹未受精神分裂症影响）和三对健康双胞胎（兄弟姐妹均患有精神分裂症）中获得了成纤维细胞。是健康的）。我们为这三组精神分裂症患者、未受影响的双胞胎和健康双胞胎准备了 iPSC 模型。当研究开始时，这对双胞胎被认为是健康且未受影响的，但这对双胞胎后来都被诊断出患有抑郁症。重新编程的 iPSC 分化为海马神经元，以测量患者的神经生理异常情况。我们发现，来自精神分裂症患者的神经元树状结构较少，兴奋性低，具有不成熟的尖峰特征，并且突触活性显着降低，突触相关基因失调。有趣的是，来自没有患有精神分裂症的双胞胎兄弟姐妹的神经元形成了另一个不同的组，该组不同于受影响的双胞胎兄弟姐妹组中的神经元，也不同于对照双胞胎组中的神经元。重要的是，它们的突触活动没有受到影响。我们从精神分裂症患者及其同卵双胞胎中获得的测量结果，并与对照健康双胞胎进行比较，表明海马突触缺陷是精神分裂症的一个核心机制。