Mechanisms of Dendritic Spine Elimination

树突棘消除机制

基本信息

  • 批准号:
    7728918
  • 负责人:
  • 金额:
    $ 29.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-08-01 至 2014-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The growth and retraction of dendritic spines with synapse formation and elimination is thought to underlie experience-dependent changes in brain circuitry during development and in the adult brain, and also may play a role in neurodevelopmental disorders. While much focus has been given to spine growth and associated synapse formation as a key step in the development of brain circuits, the mechanisms and functional implications of spine retraction have been neglected. During late postnatal development, after initial connectivity has been established, dendritic spine densities decrease and half of all synapses are lost in some regions of the cortex. This period coincides with a period of intense learning, suggesting that spine retraction and synapse elimination may have an integral role in learning and memory. The primary goal of the proposed studies is to determine the mechanisms that govern the retraction of dendritic spines and the disassembly of spine synapses during brain development, plasticity, and disease. We have three specific aims. First, we will test our hypothesis that spine retraction is induced by activity patterns that lead to synaptic weakening. Second, we will determine whether spine retraction is preceded, and possibly even initiated, by synapse disassembly. Finally, we will examine whether turnover rates of postsynaptic proteins can influence spine stability. To achieve these goals, we will use focal photolysis of caged glutamate to stimulate individual spines, combined with electrophysiology to measure consequences on spine synapse function, and dual-color time-lapse imaging to monitor the dynamics of postsynaptic proteins during spine retraction. The combined use of two-photon imaging techniques and electrophysiology of single synapses provides a novel way to identify the mechanisms that govern the retraction and disassembly of spine synapses. Results from our experiments will fill major gaps in our current understanding of neural circuit refinement during experience-dependent plasticity. Ultimately, basic knowledge of the mechanisms of spine synapse elimination has strong potential to facilitate the development of therapeutics for neurological diseases. PUBLIC HEALTH RELEVANCE: There is growing evidence that disorders in neural circuit development contribute to the etiology of many neurological diseases, including autism, schizophrenia, bipolar disorder, epilepsy, and X-linked mental retardation syndromes. The proposed experiments promise to increase our basic knowledge about the cellular and molecular mechanisms of neural circuit development in the mammalian cerebral cortex. Ultimately, such knowledge has strong potential to facilitate the development of therapeutics for human neurological diseases, such as Fragile X syndrome and autism.
描述(由申请人提供):认为突触形成和消除的树突状棘的生长和缩回被认为是经验依赖于经验的发展和成年大脑的经验依赖性变化,并且也可能在神经发育障碍中发挥作用。尽管将很大的重点放在脊柱生长和相关的突触形成中,这是脑电路发展的关键步骤,但脊柱回缩的机制和功能意义已被忽略。在产后晚期发育期间,建立了初始连通性后,树突状脊柱密度降低,所有突触的一半在皮质的某些区域中丢失。这一时期与一段激烈的学习时期相吻合,表明脊柱缩回和突触消除可能在学习和记忆中具有不可或缺的作用。拟议研究的主要目的是确定在大脑发育,可塑性和疾病期间,在脑发育,可塑性和疾病期间缩回树突状刺的机制和脊柱突触的拆卸。我们有三个具体的目标。首先,我们将检验我们的假设,即脊柱缩回是由导致突触弱化的活性模式诱导的。其次,我们将确定是否通过突触拆卸之前,甚至可能启动脊柱缩回。最后,我们将检查突触后蛋白的周转率是否会影响脊柱稳定性。为了实现这些目标,我们将使用笼中谷氨酸的局灶性光解来刺激单个棘突,并结合电生理学,以测量对脊柱突触功能的后果以及双色的延时成像,以监测脊柱回缩期间突触后蛋白的动力学。单个突触的两光子成像技术和电生理学的联合使用提供了一种新的方法来识别控制脊柱突触的缩回和拆卸的机制。我们实验的结果将填补我们当前对经验依赖性可塑性神经回路细化的理解的主要空白。最终,对脊柱突触消除机制的基本知识具有促进神经系统疾病治疗剂的强大潜力。公共卫生相关性:越来越多的证据表明,神经回路发展中的疾病有助于许多神经系统疾病的病因,包括自闭症,精神分裂症,双相情感障碍,癫痫和X连锁的智力低下综合症。提出的实验有望增加我们对哺乳动物大脑皮层神经回路发育的细胞和分子机制的基本知识。最终,这种知识具有促进人类神经疾病(例如脆弱X综合征和自闭症)的疗法发展的强大潜力。

项目成果

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Karen Zito其他文献

Karen Zito的其他文献

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{{ truncateString('Karen Zito', 18)}}的其他基金

Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    9029771
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:
Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    9511913
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:
Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    8066300
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:
Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    8600357
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:
Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    8269089
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:
Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    8293482
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:
Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    9930698
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:
Mechanisms of Dendritic Spine Elimination
树突棘消除机制
  • 批准号:
    8456903
  • 财政年份:
    2009
  • 资助金额:
    $ 29.55万
  • 项目类别:

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