Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
PLoS One. 2019 Jul 30;14(7):e0220389. doi: 10.1371/journal.pone.0220389. eCollection 2019.
Schizophrenia is a psychiatric disorder characterized by positive and negative symptoms and cognitive deficits. The exact cause of schizophrenia is still unknown, but substantial evidence indicates that it has a genetic component. Genome wide association studies demonstrate variants within miR-137 host gene are a risk factor for schizophrenia. However, the direct relationship between the pathophysiology of schizophrenia and the dosage of miR-137 remains unclear. Therefore, in this study, we generated transgenic mice overexpressing miR-137 (miR-137 Tg mice) with the neuron-specific Thy-1 promoter and examined schizophrenia-related phenotypes in these mice. Overexpression of miR-137 was observed in various brain regions of the miR-137 Tg mice, with down-regulation of putative miR-137 targets. MiR-137 Tg mice showed sensory gating deficits in a prepulse inhibition test, social deficits in a sociability and social novelty test, and cognitive deficits in a novel object recognition test. Interestingly, the predicted-altered pathways of the medial prefrontal cortex of miR-137 Tg mice were partially overlapped with those of the dorsolateral prefrontal cortex in postmortem brain of patients who died in equal to or less than 4 years after initial diagnosis of schizophrenia in published data. These results suggest that overexpression of miR-137 in the whole brain induces the several phenotypes that are relevant to aspects of psychiatric disorders, such as schizophrenia. Based on these findings, miR-137 Tg mice may have the potential to become a useful tool in researching the pathophysiology of psychiatric disorders.
精神分裂症是一种以阳性和阴性症状以及认知缺陷为特征的精神疾病。精神分裂症的确切病因仍不清楚，但大量证据表明它具有遗传成分。全基因组关联研究表明，miR-137 宿主基因内的变异是精神分裂症的一个风险因素。然而，精神分裂症的病理生理学与 miR-137 剂量之间的直接关系尚不清楚。因此，在这项研究中，我们使用神经元特异性 Thy-1 启动子生成了过表达 miR-137 的转基因小鼠（miR-137Tg 小鼠），并在这些小鼠中检查了与精神分裂症相关的表型。miR-137Tg 小鼠的各种大脑区域都观察到 miR-137 的过表达，同时下调了假定的 miR-137 靶标。miR-137Tg 小鼠在预脉冲抑制测试中表现出感觉门控缺陷，在社交性和社交新颖性测试中表现出社交缺陷，在新物体识别测试中表现出认知缺陷。有趣的是，miR-137Tg 小鼠的内侧前额叶皮层的预测改变途径与已发表数据中死后精神分裂症初诊后 4 年内死亡的患者的外侧前额叶皮层的部分重叠。这些结果表明，miR-137 在整个大脑中的过表达会引起与精神分裂症等精神疾病相关的多个表型。基于这些发现，miR-137Tg 小鼠可能有潜力成为研究精神疾病病理生理学的有用工具。
