Dopaminergic Regulation of Pyramidal Cells

锥体细胞的多巴胺能调节

基本信息

  • 批准号:
    8370366
  • 负责人:
  • 金额:
    $ 38.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-12-15 至 2017-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Among the structural changes present in schizophrenia is a decrease in dendritic spine density of pyramidal cells (PCs) in the prefrontal cortex (PFC). Glutamatergic mechanisms are critical to spine development and maintenance. Extracellular glutamate (Glu) levels are determined by a complex interplay between astrocytes and neurons, with astrocytes selectively expressing several proteins that coordinately regulate extracellular Glu. We have found that PFC dopamine (DA) denervation results in a marked decrease in dendritic spine density. We posit that cortical dopamine depletion results in increased neuronally-derived glutamatergic drive onto the dendritic spines of PFC PCs, which sets into play astrocytic mechanisms to homeostatically dampen the increase in Glu and thereby prevent further spine loss and ultimately an excito- toxic loss of neurons. In order to tes this hypothesis, we propose a series of three interrelated specific aims. We will first determine f PFC DA denervation results in changes in key astrocytic factors that modulate extracellular Glu levels, including GLT1, mGluR3, xCT, and kynurenic acid. Changes in astrocytic proteins will be compared to changes in neuronal proteins (including VGluT1 and 2, GluN1 and 2, GluA1 and 2, and EAAC1) involved in glutamatergic transmission. Protein measurements will be performed at one week after DA denervation, when dendritic spine changes have not yet occurred, and three weeks after denervation, a time when dendritic spine numbers are decreased. In the second aim we will determine if extracellular Glu levels, which are derived from both astrocytes and neurons but which do not represent synaptic Glu, are changed in the DA-denervated PFC. We will also perform physiological experiments to monitor neuronally-derived synaptic Glu activity by recording sEPSCs and evoked EPSCs from layer V PCs using whole cell patch clamping. These measurements will be performed at one and three weeks after DA denervation to determine if changes in synaptic Glu precede changes in extracellular Glu. In the final aim we will pharmacologically modify key astrocytic processes and determine if these changes prevent or reverse dendritic spine loss seen in response to DA denervation. As one example, we will determine if treatment of PFC DA-denervated animals with the antibiotic ceftriaxone (CEF), which increases expression of the astrocytic Glu transporter GLT1 and thereby decreases extracellular Glu levels, modifies the effect of DA denervation on spine number. Chronic treatment with CEF will be started on the day after DA denervation to assess prevention of spine loss. We will also start CEF treatment at three weeks after DA denervation, with drug treatment continuing for three weeks, in order to assess if induction of GLT1 attenuates or reverses spine loss once the dsytrophic changes in PC dendrites have occurred. Similarly, we will examine the effects of an mGluR2/3 receptor agonist and kynurenic acid. PUBLIC HEALTH RELEVANCE: The prefrontal cortex (PFC) of persons with schizophrenia is smaller than the PFC in persons without neurological or psychiatric disease, but there is no overall loss of cells. Instead, the architecture of cortical neurons is distorted and the cells los dendritic spines, small protrusions which receive incoming excitatory signals from other neurons. We propose that changes in astrocytes, a type of cell previously thought to be a "support" cell in the brain but now known to have much broader functions, compensates for the process that causes dendritic spine loss, and that astrocytic proteins may be novel targets for new drug therapies for schizophrenia.
描述(由申请人提供):在精神分裂症中存在的结构变化中,是前额叶皮层(PFC)中金字塔细胞(PC)的树突状脊柱密度降低。谷氨酸能机制对于脊柱发育和维护至关重要。细胞外谷氨酸(GLU)水平取决于星形胶质细胞和神经元之间的复杂相互作用,星形胶质细胞选择性地表达了几种协同调节细胞外GLU的蛋白质。我们发现PFC多巴胺(DA)的神经保护导致树突状脊柱密度显着降低。我们认为,皮质多巴胺的消耗会导致神经源性的谷氨酸能驱动到PFC PC的树突状刺,从而使其变为易发的星形胶质细胞机制,从而使GLU的增加降低了GLU的增加,从而导致脊柱的增加,从而防止了进一步的神经毒性损失,并最终导致神经毒性的神经损失。为了提及这一假设,我们提出了一系列相互关联的特定目标。 我们将首先确定F PFC DA的神经性会导致关键星形胶质细胞因子调节细胞外GLU水平的变化,包括GLT1,MGLUR3,XCT和Kynurenic Acid。星形胶质细胞蛋白的变化将与神经元蛋白的变化(包括VGLUT1和2,Glun1和2,GluA1和2以及EAAC1)的变化进行比较。蛋白质的测量将在DA神经膜发生后的一周后进行,当时尚未发生树突状脊柱的变化,而在神经支配后三周,这是树突状脊柱数量减少的时期。 在第二个目标中,我们将确定在DA否决的PFC中更改了来自星形胶质细胞和神经元但不代表突触GLU的细胞外GLU水平。我们还将通过使用全细胞斑块夹紧记录SEPCS并从V层V PC中记录SEPC并诱发EPSC来监测神经源性的突触GLU活性。这些测量结果将在DA去神经后的1和三周内进行,以确定突触GLU的变化是否在细胞外GLU的变化之前。 在最终目的中,我们将在药理上修改关键的星形胶质细胞过程,并确定这些变化是否可以防止对DA神经的响应响应DA的脊柱损失。作为一个例子,我们将确定用抗生素头孢曲松(CEF)对PFC DANEVER的动物的处理是否增加了星形胶质细胞GLU转运蛋白GLT1的表达,从而降低了细胞外GLU水平,从而改变了DA DAERAVERTION对脊柱数量的影响。 DA Denervation的第二天,将开始使用CEF进行慢性治疗,以评估预防脊柱损失。我们还将在DA去神经治疗后三周开始CEF治疗,并持续三周,以评估GLT1的诱导是否会减弱或逆转一旦PC树突中的枝状变化发生。同样,我们将检查MGLUR2/3受体激动剂和Kynurenic酸的作用。 公共卫生相关性:精神分裂症患者的前额叶皮层(PFC)小于没有神经或精神病的人的PFC,但总体上没有细胞损失。取而代之的是,皮质神经元的结构被扭曲,细胞los树突状刺,小突起,这些突起接收来自其他神经元的传入兴奋性信号。我们提出,星形胶质细胞的变化是一种以前被认为是大脑中的“支持”细胞的细胞,但现在已知具有更广泛的功能,可以补偿导致树突状脊柱损失的过程,而星形胶质细胞蛋白可能是针对精神分裂症的新药物疗法的新靶标。

项目成果

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ARIEL Y DEUTCH其他文献

ARIEL Y DEUTCH的其他文献

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{{ truncateString('ARIEL Y DEUTCH', 18)}}的其他基金

The role of claustrum in substance abuse and cognition
屏状核在药物滥用和认知中的作用
  • 批准号:
    7700693
  • 财政年份:
    2009
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dopaminergic Regulation of Pyramidal Cells
锥体细胞的多巴胺能调节
  • 批准号:
    7526361
  • 财政年份:
    2006
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dopaminergic Regulation of Pyramidal Cells
锥体细胞的多巴胺能调节
  • 批准号:
    8507274
  • 财政年份:
    2006
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dopaminergic Regulation of Pyramidal Cells
锥体细胞的多巴胺能调节
  • 批准号:
    8660073
  • 财政年份:
    2006
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dopaminergic Regulation of Pyramidal Cells
锥体细胞的多巴胺能调节
  • 批准号:
    7993553
  • 财政年份:
    2006
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dopaminergic Regulation of Pyramidal Cells
锥体细胞的多巴胺能调节
  • 批准号:
    7208450
  • 财政年份:
    2006
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dopaminergic Regulation of Pyramidal Cells
锥体细胞的多巴胺能调节
  • 批准号:
    7743109
  • 财政年份:
    2006
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dendritic Plasticity in Parkinson's Disease
帕金森病的树突可塑性
  • 批准号:
    6766759
  • 财政年份:
    2002
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dopamine and dendritic spines
多巴胺和树突棘
  • 批准号:
    6614253
  • 财政年份:
    2002
  • 资助金额:
    $ 38.97万
  • 项目类别:
Dendritic Plasticity in Parkinson's Disease
帕金森病的树突可塑性
  • 批准号:
    6918501
  • 财政年份:
    2002
  • 资助金额:
    $ 38.97万
  • 项目类别:

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