{"title":"特发性精神分裂症患者神经元的异常连接和网络活动。","authors":"","doi":"10.1016/j.nbd.2024.106678","DOIUrl":null,"url":null,"abstract":"<div><div>Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from <em>postmortem</em> brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and <em>E</em>-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Aberrant neuronal connectivity and network activity of neurons derived from patients with idiopathic schizophrenia\",\"authors\":\"\",\"doi\":\"10.1016/j.nbd.2024.106678\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from <em>postmortem</em> brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and <em>E</em>-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization.</div></div>\",\"PeriodicalId\":19097,\"journal\":{\"name\":\"Neurobiology of Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2024-09-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurobiology of Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S096999612400278X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Disease","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S096999612400278X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
精神分裂症(SCZ)是一种与遗传因素密切相关的精神疾病。解释该病病因的一个主要假说是与兴奋-抑制不平衡的突触传递相关的突触功能障碍,最终导致与该病相关的网络振荡受损和认知障碍。在这里,我们研究了一种高度定义的GABA能和谷氨酸能神经元共培养物的形态和功能特性,该共培养物来自特发性SCZ患者的诱导多能干细胞(iPSC)。我们的研究结果表明,在共培养物中,GABA能神经元的突触基因上调,兴奋性突触形成增加。与此同时,我们观察到轴突初段的长度减少,这与 SCZ 患者死后大脑的数据一致。与突触密度增加相一致的是,贴片钳分析显示,从GABA能SCZ神经元记录到的自发兴奋突触后电流(EPSC)明显增加。最后,神经元网络的 MEA 记录显示,网络活动强度增加,这可能是对共培养物中突触传递和 E-I 平衡改变的反应。总之,我们的研究结果表明,SCZ 样本中神经元活动的选择性失调为突触形成和突触传递的改变提供了证据,而突触形成和突触传递的改变是网络同步异常的潜在基础。
Aberrant neuronal connectivity and network activity of neurons derived from patients with idiopathic schizophrenia
Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and E-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization.
期刊介绍:
Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.