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：
LORI Lynn MCMAHON
金额：
$ 29.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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

来源：
https://reporter.nih.gov/project-details/8850751
关键词：
Acetylcholine Address Adrenergic Agents Adrenergic Fibers Age Aging Agonist Alzheimer&apos s Disease Amyloid beta-Protein Animal Model Animals Appearance Axon Behavioral Assay Bilateral Biochemistry Brain Cerebrospinal Fluid Cerebrum Cholinergic Fibers Clinical Trials Conflict (Psychology)Data Denervation Development Disease Disease Progression Electrophysiology (science)Fiber Functional disorder Funding Ganglia Ganglionectomy Growth Hippocampus (Brain)Human Image Immunohistochemistry Impaired cognition Label Lead Learning Lesion Long-Term Depression Medial Memory Memory Loss Memory impairment Muscarinic Acetylcholine Receptor Muscarinic M1 Receptor Muscarinic M3 Receptor Neurons Patients Phenotype Progress Reports Publishing Rattus Reporting Risk Factors Rodent Model Role Side Signal Transduction Slice Staging Structure of superior cervical ganglion Synapses Synaptic plasticity System Testing Toxic effect Transgenic Mice Visual abeta accumulation acetylcholine transporter adrenergic age related amyloid precursor protein processing basal forebrain cholinergic neurons cholinergic cholinergic neuron density feeding in vivo mild cognitive impairment mouse model nerve supply new therapeutic target noradrenergic novel prevent receptor function reinnervation repaired retrograde transport secretase

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）：衰老是阿尔茨海默氏病（AD）发展的最大危险因素。与年龄相关的基础前脑胆碱能神经元的变性和淀粉样蛋白β（A？）的积累大大加速了AD，导致认知能力下降。最新数据表明胆碱能功能障碍与A之间存在关键的双向关系？毒性。胆碱能神经元对A的毒性作用非常敏感，而毒蕈碱受体功能（MACHR）功能（尤其是M1和M3受体）的缺陷会导致淀粉样前体蛋白蛋白（APP）的淀粉样蛋白生成加工增加。但是，尽管A之间存在明显的相互作用？胆碱能系统，关于其精确相互作用的机械理解远远不清楚。重要的是，在体内施用的M1 MACHR激动剂会减少A？在AD患者和AD小鼠模型的脑脊柱中，强调了在衰老和AD中保持M1受体功能的重要性。在啮齿动物模型中，胆碱能变性刺激了一个显着的神经元重排，其中从宫颈上颈神经节发芽到海马和皮质的脱腐状区域的去甲肾上腺素能交感神经纤维。重要的是，在AD患者的海马中已经证明了交感神经发芽，并在初步研究中得到了我们的证实。在最后一个融资周期中，我们发现海马中的“新”胆碱能纤维发芽，这些胆碱能纤维完全取决于SCG的交感神经甲肾上腺素能纤维的发芽。这些新纤维的外观与CA3-CA1突触时的M1受体依赖性LTD的营救有关。这一发现表明，在年龄和疾病相关的胆碱能变性期间，已经建立了内源性的“修复”机制来维持M1受体功能和突触可塑性。这一发现可以为矛盾的动物研究提供解释，以评估胆碱能变性对海马依赖学习和记忆的影响。此外，这种胆碱能加剧可能导致疾病早期AD患者观察到的胆碱能活性的增加。在这种竞争性更新中，我们将采用多方面的方法，包括行为测定，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颖问题：海马交感神经促进生长和伴随的胆碱性促进性依赖性的依赖性和记忆力依赖于记忆的依赖性，并涉及辅助依赖的含量？ “新的”胆碱能纤维是否功能性，并且会导致M1 MACHR功能，MLTD和学习的营救吗？有吗？胆碱能变性的动物积聚直接干扰MACHR信号传导，MLTD诱导/表达和交感神经发芽？这些研究的结果预计将证实交感神经发芽在胆碱能变性过程中维持海马功能方面的有益作用，从而为治疗衰老和AD的认知能力下降提供了一种新颖的治疗靶标。