Novel Split GFP Based Intersynaptic Markers to Study Synaptic Specificity in vivo

基于新型分裂 GFP 的突触间标记用于研究体内突触特异性

基本信息

  • 批准号:
    7486600
  • 负责人:
  • 金额:
    $ 3.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-02-04 至 2008-08-20
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The nervous system is composed of highly complex circuits that govern thought and behavior. To ensure correct circuit formation, neurons must identify appropriate synaptic targets among the many neurites they contact before forming synaptic connections. Altered synaptogenesis is thought to play a role in disorders such as schizophrenia and autism. Despite its central role in circuit formation, synaptic specificity is poorly understood. I have developed a novel way to visualize synapses between specific neurons in vivo. I propose to use this method and take advantage of the simple, well-characterized nervous system of C. elegans to elucidate molecular mechanisms that underlie this fundamental process. I then propose to extend this my findings to mammalian neurons. This proposal is relevant to the NINDS mission to support basic research in fields related to the causes of neurological disorders, and the NIMH mission to support research on mental disorders and the underlying basic science of brain and behavior. My specific aims are: 1) to visualize changes in synaptic connectivity between a specific pair of pre- and postsynaptic neurons in C. elegans, 2) to discover the molecular determinants of synaptic specificity in this system, and 3) to adapt this new labeling method to mammalian neurons. To visualize changes in synaptic connectivity, I have developed an intersynaptic marker. I have fused complementary fragments of a split GFP to pre- and postsynaptically localized proteins, expressed under cell-specific promoters. I have successfully visualized changes in connectivity in two well-characterized circuits in C. elegans using known synaptic specificity mutants. I am interested in how synaptic specificity is regulated in complex environments, such as nerve bundles, where parallel neurites must distinguish among multiple potential targets to form appropriate connections. Therefore I am now adapting the intersynaptic marker to label synaptic connections between a specific neuron pair in a posterior nerve bundle. I will take an unbiased genetic approach to discover molecular mechanisms guiding synaptic specificity in this system, utilizing this marker to detect defects in connectivity. Finally, I am developing the intersynaptic marker for use in cultured mammalian cortical neurons. Insights gained from this study will aid in understanding synaptic specificity in the complex environments of the vertebrate nervous system. Understanding the mechanisms that regulate circuit formation will bring us closer to understanding and treating neurological diseases.
描述(由申请人提供):神经系统由控制思想和行为的高度复杂的电路组成。为了确保正确的电路形成,神经元必须在形成突触连接之前,在它们接触的许多神经突中识别合适的突触目标。突触发生的改变被认为在精神分裂症和自闭症等疾病中起着重要作用。尽管突触特异性在电路形成中起着核心作用,但人们对其了解甚少。我发明了一种新的方法来可视化体内特定神经元之间的突触。我建议使用这种方法,并利用秀丽隐杆线虫简单、特征明确的神经系统来阐明这一基本过程背后的分子机制。然后,我建议将我的发现扩展到哺乳动物神经元。该提案与NINDS的使命有关,即支持与神经系统疾病病因相关领域的基础研究,以及NIMH的使命,即支持精神障碍研究以及大脑和行为的潜在基础科学。我的具体目标是:1)可视化秀丽隐杆线虫中一对特定的突触前和突触后神经元之间突触连接的变化,2)发现该系统中突触特异性的分子决定因素,3)将这种新的标记方法应用于哺乳动物神经元。为了可视化突触连通性的变化,我发明了一种突触间标记。我已经将一个分裂的GFP的互补片段融合到突触前和突触后定位的蛋白中,这些蛋白在细胞特异性启动子下表达。我已经成功地利用已知的突触特异性突变体在秀丽隐杆线虫的两个特征良好的电路中可视化了连通性的变化。我感兴趣的是突触特异性是如何在复杂的环境中被调节的,比如神经束,在神经束中,平行的神经突必须区分多个潜在的目标以形成适当的连接。因此,我现在采用突触间标记来标记后神经束中特定神经元对之间的突触连接。我将采用无偏见的遗传学方法来发现引导该系统突触特异性的分子机制,利用该标记来检测连接缺陷。最后,我正在开发用于培养哺乳动物皮质神经元的突触间标记物。从这项研究中获得的见解将有助于理解脊椎动物神经系统复杂环境中的突触特异性。了解调节神经回路形成的机制将使我们更接近于理解和治疗神经系统疾病。

项目成果

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Miri Kerensa VanHoven其他文献

Miri Kerensa VanHoven的其他文献

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{{ truncateString('Miri Kerensa VanHoven', 18)}}的其他基金

Molecular Mechanisms of Neural Circuit Formation
神经回路形成的分子机制
  • 批准号:
    8009514
  • 财政年份:
    2010
  • 资助金额:
    $ 3.07万
  • 项目类别:
Molecular Mechanisms of Neural Circuit Formation
神经回路形成的分子机制
  • 批准号:
    8399728
  • 财政年份:
    2010
  • 资助金额:
    $ 3.07万
  • 项目类别:
Molecular Mechanisms of Neural Circuit Formation
神经回路形成的分子机制
  • 批准号:
    8842653
  • 财政年份:
    2010
  • 资助金额:
    $ 3.07万
  • 项目类别:
Molecular Mechanisms of Neural Circuit Formation
神经回路形成的分子机制
  • 批准号:
    8206628
  • 财政年份:
    2010
  • 资助金额:
    $ 3.07万
  • 项目类别:
Molecular Mechanisms of Neural Circuit Formation
神经回路形成的分子机制
  • 批准号:
    7761794
  • 财政年份:
    2010
  • 资助金额:
    $ 3.07万
  • 项目类别:
Molecular Mechanisms of Neural Circuit Formation
神经回路形成的分子机制
  • 批准号:
    8996175
  • 财政年份:
    2010
  • 资助金额:
    $ 3.07万
  • 项目类别:

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    2007
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