Muscarinic receptor induced LTD in rat hippocampus

毒蕈碱受体诱导大鼠海马LTD

基本信息

  • 批准号:
    8850751
  • 负责人:
  • 金额:
    $ 29.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-01-01 至 2016-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Aging is the biggest risk factor for the development of Alzheimer's disease (AD). Age-related degeneration of basal forebrain cholinergic neurons and accumulation of amyloid beta (A?) are greatly accelerated in AD, contributing to cognitive decline. Recent data suggests a critical bidirectional relationship between cholinergic dysfunction and A? toxicity. Cholinergic neurons are exquisitely sensitive to the toxic effects of A?, while deficits in muscarinic receptor (mAChR) function, particularly M1 and M3 receptors, leads to increased amyloidogenic processing of amyloid precursor protein (APP). However, despite obvious interactions between A? and the cholinergic system, a mechanistic understanding regarding their precise interactions is far from clear. Importantly, M1 mAChR agonists administered in vivo decrease A? in cerebral spinal fluid of AD patients and in AD mouse models, highlighting the importance of maintaining M1 receptor function in aging and in AD. In rodent models, cholinergic degeneration stimulates a remarkable neuronal rearrangement where noradrenergic sympathetic fibers from the superior cervical ganglia sprout into denervated regions of hippocampus and cortex. Importantly, sympathetic sprouting has been demonstrated in hippocampus of AD patients and confirmed by us in preliminary studies. During the last funding cycle, we discovered sprouting of "new" cholinergic fibers in hippocampus that are completely dependent upon sprouting of sympathetic noradrenergic fibers from the SCG. The appearance of these new fibers correlates with the rescue of a M1 receptor dependent LTD at CA3-CA1 synapses. This finding indicates that an endogenous "repair" mechanism is in place to maintain M1 receptor function and synaptic plasticity during age- and disease-related cholinergic degeneration. This discovery could offer an explanation for conflicting animal studies assessing the impact of cholinergic degeneration on hippocampal dependent learning and memory. Moreover, this cholinergic reinnervation could be responsible for the increase in cholinergic activity observed in AD patients in early stages of the disease. In this competitive renewal, we will use a multifaceted approach including behavioral assays, brain slice electrophysiology, biochemistry, immunohistochemistry and confocal imaging to address the following novel questions: Does hippocampal sympathetic sprouting and accompanying cholinergic reinnervation rescue hippocampal dependent learning and memory deficits induced by cholinergic denervation? Are the "new" cholinergic fibers functional and do they cause the rescue of M1 mAChR function, mLTD, and learning? Does A? accumulation in animals with cholinergic degeneration directly interfere with mAChR signaling, mLTD induction/expression, and sympathetic sprouting? The results of these studies are expected to confirm a beneficial role of sympathetic sprouting in maintaining hippocampal function during cholinergic degeneration, thus providing a novel therapeutic target for the treatment of cognitive decline in aging and in AD.
描述(由申请人提供):衰老是阿尔茨海默病(AD)发展的最大危险因素。AD患者基底前脑胆碱能神经元的年龄相关变性和β淀粉样蛋白(A?)的积累大大加速,导致认知能力下降。最近的数据表明胆碱能功能障碍与a ?毒性。胆碱能神经元对A?而毒蕈碱受体(mAChR)功能的缺陷,特别是M1和M3受体,导致淀粉样蛋白前体蛋白(APP)的淀粉样变性加工增加。然而,尽管A?至于胆碱能系统,对它们精确相互作用的机制理解还远不清楚。重要的是,体内给药M1 mAChR激动剂可降低A?在阿尔茨海默病患者的脑脊液和阿尔茨海默病小鼠模型中,强调了维持M1受体功能在衰老和阿尔茨海默病中的重要性。在啮齿类动物模型中,胆碱能变性刺激了显著的神经元重排,来自颈上神经节的去肾上腺素能交感神经纤维萌发到海马体和皮质的去神经区。重要的是,我们已经在AD患者的海马体中发现了交感神经萌芽,并在初步研究中得到了证实。在上一个资助周期中,我们发现海马体中“新”胆碱能纤维的萌发完全依赖于来自SCG的交感去肾上腺素能纤维的萌发。这些新纤维的出现与CA3-CA1突触M1受体依赖性LTD的恢复有关。这一发现表明,内源性“修复”机制在年龄和疾病相关的胆碱能变性期间维持M1受体功能和突触可塑性。这一发现可以为评估胆碱能变性对海马依赖性学习和记忆的影响的相互矛盾的动物研究提供解释。此外,这种胆碱能神经再生可能是AD患者在疾病早期观察到的胆碱能活性增加的原因。在这一竞争性更新中,我们将使用多方面的方法,包括行为分析、脑切片电生理学、生物化学、免疫组织化学和共聚焦成像来解决以下新问题:海马交感神经芽化和伴随的胆碱能再神经支配是否能拯救由胆碱能去神经支配引起的海马依赖性学习和记忆缺陷?“新”胆碱能纤维是否有功能?它们是否导致M1、mAChR功能、mLTD和学习功能的恢复?一个什么?胆碱能变性动物体内的蓄积直接干扰mAChR信号、mLTD诱导/表达和交感神经发芽?这些研究结果有望证实交感神经芽在维持胆碱能变性期间海马功能中的有益作用,从而为治疗衰老和AD的认知能力下降提供新的治疗靶点。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sympathetic sprouting in visual cortex stimulated by cholinergic denervation rescues expression of two forms of long-term depression at layer 2/3 synapses.
  • DOI:
    10.1016/j.neuroscience.2010.04.027
  • 发表时间:
    2010-07-14
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    McCoy, P. A.;McMahon, L. L.
  • 通讯作者:
    McMahon, L. L.
Estradiol and the relationship between dendritic spines, NR2B containing NMDA receptors, and the magnitude of long-term potentiation at hippocampal CA3-CA1 synapses.
  • DOI:
    10.1016/j.psyneuen.2009.06.003
  • 发表时间:
    2009-12
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Smith, Caroline C;Vedder, Lindsey C;McMahon, Lori L
  • 通讯作者:
    McMahon, Lori L
Noradrenergic sympathetic sprouting and cholinergic reinnervation maintains non-amyloidogenic processing of AβPP.
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LORI Lynn MCMAHON其他文献

LORI Lynn MCMAHON的其他文献

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{{ truncateString('LORI Lynn MCMAHON', 18)}}的其他基金

Consequences of Noradrenergic Degeneration in the Novel TgF344-AD Rat Model
新型 TgF344-AD 大鼠模型中去甲肾上腺素能变性的后果
  • 批准号:
    10581841
  • 财政年份:
    2020
  • 资助金额:
    $ 29.13万
  • 项目类别:
Consequences of Noradrenergic Degeneration in the Novel TgF344-AD Rat Model
新型 TgF344-AD 大鼠模型中去甲肾上腺素能变性的后果
  • 批准号:
    10621852
  • 财政年份:
    2020
  • 资助金额:
    $ 29.13万
  • 项目类别:
Impact of estrogen loss and replacement on GluN2B containing NMDARs, synaptic plasticity, and learning and memory in females using a novel transgenic rat model of Alzheimer’s Disease
使用新型阿尔茨海默病转基因大鼠模型,研究雌激素损失和替代对含有 NMDAR 的 GluN2B、突触可塑性以及女性学习和记忆的影响
  • 批准号:
    9128361
  • 财政年份:
    2016
  • 资助金额:
    $ 29.13万
  • 项目类别:
Estrogen and hippocampal plasticity
雌激素和海马可塑性
  • 批准号:
    7849770
  • 财政年份:
    2008
  • 资助金额:
    $ 29.13万
  • 项目类别:
Estrogen and hippocampal plasticity
雌激素和海马可塑性
  • 批准号:
    8109411
  • 财政年份:
    2008
  • 资助金额:
    $ 29.13万
  • 项目类别:
Estrogen and hippocampal plasticity
雌激素和海马可塑性
  • 批准号:
    8257977
  • 财政年份:
    2008
  • 资助金额:
    $ 29.13万
  • 项目类别:
Estrogen and hippocampal plasticity
雌激素和海马可塑性
  • 批准号:
    7643164
  • 财政年份:
    2008
  • 资助金额:
    $ 29.13万
  • 项目类别:
Muscarinic receptor induced LTD in rat hippocampus
毒蕈碱受体诱导大鼠海马LTD
  • 批准号:
    8205782
  • 财政年份:
    2004
  • 资助金额:
    $ 29.13万
  • 项目类别:
Muscarinic Receptor Induced LTD in Rat Hippocampus
大鼠海马毒蕈碱受体诱导的LTD
  • 批准号:
    6838750
  • 财政年份:
    2004
  • 资助金额:
    $ 29.13万
  • 项目类别:
Muscarinic receptor induced LTD in rat hippocampus
毒蕈碱受体诱导大鼠海马LTD
  • 批准号:
    8318052
  • 财政年份:
    2004
  • 资助金额:
    $ 29.13万
  • 项目类别:

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