中国科学院上海生命科学研究院神经科学研究所机构知识库
Advanced  
SIBS OpenIR  > 神经所(总)  > 学位论文
Title: BDNF-TrkB信号通路在突触传递稳态调控中的作用
Author: 贾洁敏
Degree Level: 博士
Issued Date: 2008-10-15
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 熊志奇
Keyword: 脑起源神经营养因子 ; TrkB 受体 ; 泛素-蛋白酶体 ; 稳态调节 ; 突触蛋白质成份重组 ; 神经元活动状态
Alternative Title: BDNF-TRKB SIGNALING ROLES IN HOMEOSTATIC REGULATION OF SYNAPTIC TRANSMITTION
Major: 神经生物学
Abstract: 当外界刺激导致神经元活性状态长期处于极限状态时,突触传递会启动强大的稳态调节能力,这对于神经系统功能的正常行使和神经网络的稳定有着至关重要的作用,然而其分子机理尚不清楚。本研究发现,在体外原代培养的大鼠海马和皮层神经元中,长期改变神经元活动状态可导致脑起源神经营养因子(Brain-Derived Neurotrophin Factor,BDNF)表达水平、TrkB受体磷酸化水平和突触蛋白质表达水平的改变。BDNF表达的变化依赖于受神经元活性调节的TORC1(Transducer Of Regulated CREB-bingding protein 1)的磷酸化状态和亚细胞定位的改变。外源BDNF可以挽回由于长期抑制神经元电活动发放所导致的突触蛋白质组成的改变,并且抑制TrkB受体活性或清除内源性BDNF可以阻断由于长期提高神经元活性状态而引起的突触蛋白质组成的改变。不同的BDNF下游信号通路负责不同种类的突触蛋白质的改变。而且本研究亦发现外源BDNF足以增加突触蛋白质的泛素化,而抑制内源性BDNF-TrkB 信号可抑制由于长期神经元电活动升高而引起的突触蛋白质泛素化的增加,BDNF-TrkB信号通路既是活性依赖的突触蛋白质泛素化的充分条件又是必要条件。长期抑制蛋白酶体的蛋白水解活性可下调神经元静息状态下的微兴奋性突触后电位(mEPSC)的电流幅度,即为Synaptic Scaling 中的Scaling Down。本研究还发现神经活性除了可以调节突触传递以外,也会调节和细胞兴奋性息息相关的钾通道Kv2.1在细胞膜上的表达。本研究主要阐述了在中枢系统神经元中,BDNF-TrkB信号通路通过调节泛素-蛋白酶体(UPS)进而介导了神经电活动依赖的突触蛋白质成份重组和突触传递的稳态调节。
English Abstract: Homeostatic regulation of synaptic properties in response to chronic alteration of neuronal activity is essential for neural circuit function and stability, but the underlying molecular mechanism is largely unknown. Here we found that changes of neuronal activity led to corresponding alterations in the expression of brain-derived neurotrophic factor (BDNF) and TrkB phosphorylation, as well as in the level of synaptic proteins. The changes of BDNF expression were dependent on subcellular location and phosphorylation level of TORC 1 (Transducer Of Regulated CREB-bingding protein 1). Exogenous BDNF reversed changes in synaptic proteins induced by chronic activity blockade, while Trk inhibition or depleting endogenous BDNF blocked the changes of these proteins induced by chronic activity elevation. Different downstream pathways of BDNF signaling were found to be responsible for modulating different sets of proteins. Furthermore, exogenous BDNF was sufficient to increase ubiquitination of synaptic proteins, whereas inhibition of endogenous BDNF-TrkB prevented ubiquitination of synaptic proteins induced by chronic elevation of neuronal activity. Chronic inhibition of proteasome led to down-regulation of amplitude of mEPSC, which is defined as Scaling Down of Synaptic Scaling. Neuronal activity modulation also changed potassium channel Kv2.1 membrane expression, which has major contribution to neural excitability. Thus BDNF-TrkB signaling acts upstream from ubiquitin proteasome system (UPS), mediating homeostatic regulation of synaptic protein reorganization and synaptic transmission.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2363
Appears in Collections:神经所(总)_学位论文

Files in This Item:
File Name/ File Size Content Type Version Access License
10001_200418010015150贾洁敏_paper.doc(11376KB)----暂不开放 联系获取全文

Recommended Citation:
BDNF-TrkB信号通路在突触传递稳态调控中的作用.贾洁敏[d].中国科学院上海生命科学研究院,2008.20-25
Service
Recommend this item
Sava as my favorate item
Show this item's statistics
Export Endnote File
Google Scholar
Similar articles in Google Scholar
[贾洁敏]'s Articles
CSDL cross search
Similar articles in CSDL Cross Search
[贾洁敏]‘s Articles
Related Copyright Policies
Null
Social Bookmarking
Add to CiteULike Add to Connotea Add to Del.icio.us Add to Digg Add to Reddit
所有评论 (0)
暂无评论
 
评注功能仅针对注册用户开放,请您登录
您对该条目有什么异议,请填写以下表单,管理员会尽快联系您。
内 容:
Email:  *
单位:
验证码:   刷新
您在IR的使用过程中有什么好的想法或者建议可以反馈给我们。
标 题:
 *
内 容:
Email:  *
验证码:   刷新

Items in IR are protected by copyright, with all rights reserved, unless otherwise indicated.

 

 

Valid XHTML 1.0!