高表达NRG1损坏树突棘发育的研究

发布时间：2018-02-26 23:05

本文关键词： NRG1 精神分裂症 ErbB4 树突棘　出处：《南昌大学》2017年硕士论文　论文类型：学位论文

【摘要】：精神分裂症(Schizophrenia,SCZ)是一种严重的精神疾病,发病率占世界人口的1%。目前对SCZ的病因并不十分清楚,更多的证据表明遗传因素在SCZ中起着重要作用。最近遗传学的研究,已经鉴定人类染色体上的很多区域以及基因同SCZ相关,其中神经调节素1(Neuregulin1,NRG1)及其受体Erb B4的编码基因是较早被发现并被公认的两个SCZ易感基因。目前,在人类NGR1基因中大部分与精神分裂症相关的单核苷酸多态性(SNPs)位于内含子中,即NRG1中碱基的改变并不影响其编码产物NRG1的氨基酸组成,这些SNPs如何导致精神分裂症并不清楚,从而提示SNPs很有可能通过调节NRG1的表达而导致SCZ。有研究发现在SCZ病人的前额叶皮层和海马区NRG1的m RNA和蛋白水平升高,NRG1/Erb B4信号通路的活性在SCZ病人的前脑区也有所增加。相对应地,过表达NRG1的转基因鼠也会表现出SCZ相关的行为学缺陷。但是NRG1高表达导致SCZ的机制并不清楚,为了探索两者之间的联系,我们实验室构建了一种仅在前脑区域过表达NRG1的转基因小鼠(cto Nrg1小鼠)。首先我们记录了cto Nrg1小鼠前额叶皮层锥体神经元微小兴奋性突触后电流(m EPSC),发现频率显著降低。m EPSC频率的降低说明突触前谷氨酸释放的减少或者突触数目的减少。体外培养的海马神经元中高表达NRG1,树突棘的密度显著降低,而且降低的程度与NRG1过表达水平呈剂量依赖效应。cto Nrg1小鼠的高尔基染色观察到,其前额叶和海马的树突棘密度有显著性降低。之前的报道LIMK1参与了树突棘的形成与发育。NRG1的胞内结构域能够同LIMK1结合。PSD实验观察到NRG1定位于突触后膜,而且过表达NRG1促进LIMK1/cofilin信号通路。进一步发现,在过表达NRG1的原代海马神经元中加入LIMK1抑制剂DMN(Damnacaanthl)后,可以缓解过表达NRG1引起的树突棘密度降低。本研究显示NRG1过表达使LIMK1过度激活,引起树突棘发育异常并参与SCZ发病。
[Abstract]:Schizophrenia (Schizophrenia) is a serious mental disease with an incidence of 1. 1% of the world's population. The etiology of SCZ is not well understood. There is more evidence that genetic factors play an important role in SCZ. It has been identified that many regions and genes on human chromosomes are associated with SCZ, in which neuromodulin 1Neuregulin 1NRG1) and its receptor Erb B4 are two previously identified and recognized SCZ susceptibility genes. Most of the single nucleotide polymorphisms associated with schizophrenia (SNPs) in human NGR1 genes are located in introns, meaning that changes in the bases in NRG1 do not affect the amino acid composition of its encoded product, NRG1, and it is not clear how these SNPs cause schizophrenia. It is suggested that SNPs may result in SCZs by regulating the expression of NRG1. Some studies have found that m RNA and protein levels of NRG1 in the prefrontal cortex and hippocampal area of patients with SCZ increase the activity of NRG1 / Erb B4 signaling pathway in the forebrain region of SCZ patients. Correspondingly, Transgenic mice with overexpression of NRG1 also showed behavioral defects associated with SCZ. However, the mechanism of high expression of NRG1 leading to SCZ is not clear, in order to explore the relationship between the two. We have constructed a transgenic Nrg1 mouse with NRG1 overexpression only in the forebrain region. First, we recorded the minimal excitatory postsynaptic current of the pyramidal neurons in the prefrontal cortex of cto Nrg1 mice and found that the frequency was significant. The decrease of .m EPSC frequency indicated that the presynaptic glutamate release decreased or the number of synapses decreased. In vitro cultured hippocampal neurons overexpressed NRG1, and the density of dendritic spine decreased significantly. Moreover, the degree of decrease was in a dose-dependent manner with the overexpression of NRG1. Golgi staining of Nrg1 mice was observed. The density of dendritic spine in prefrontal lobe and hippocampus was significantly decreased. It was previously reported that LIMK1 was involved in the formation and development of dendritic spine. The intracellular domain of NRG1 could bind with LIMK1. It was observed that NRG1 was localized in postsynaptic membrane. Furthermore, overexpression of NRG1 promoted the LIMK1/cofilin signaling pathway. It was further found that LIMK1 inhibitor DMNa-Damnacaanthl was added to the primary hippocampal neurons overexpression of NRG1. This study showed that overexpression of NRG1 caused excessive activation of LIMK1, leading to abnormal development of dendritic spine and involvement in the pathogenesis of SCZ.
【学位授予单位】：南昌大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.3

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