Muscarinic receptor induced LTD in rat hippocampus

描述（由申请人提供）：衰老是阿尔茨海默病（AD）发展的最大风险因素。基底前脑胆碱能神经元变性和β淀粉样蛋白（A？）在AD中大大加速，导致认知能力下降。最近的数据表明，胆碱能功能障碍和A？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（mAChR）功能的缺陷，特别是M1和M3受体，导致淀粉样前体蛋白（APP）的淀粉样形成加工增加。然而，尽管A？和胆碱能系统，关于它们的精确相互作用的机制理解还远不清楚。重要的是，M1 mAChR激动剂在体内给药减少A？在AD患者和AD小鼠模型的脑脊液中，强调了在衰老和AD中维持M1受体功能的重要性。 在啮齿类动物模型中，胆碱能变性刺激显著的神经元重排，其中来自上级颈神经节的去甲肾上腺素能交感神经纤维发芽进入海马和皮质的去神经支配区域。重要的是，交感神经萌芽已被证明在AD患者的海马，并证实了我们在初步研究。在上一个资助周期中，我们发现海马中“新”胆碱能纤维的发芽完全依赖于SCG交感去甲肾上腺素能纤维的发芽。这些新纤维的出现与CA 3-CA 1突触处M1受体依赖性LTD的拯救相关。这一发现表明，内源性“修复”机制是在适当的位置，以维持M1受体功能和突触可塑性在年龄和疾病相关的胆碱能变性。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，这种胆碱能神经再支配可能是负责增加胆碱能活性观察到AD患者在疾病的早期阶段。 在这个竞争性的更新，我们将使用多方面的方法，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，以解决以下新的问题：海马交感神经发芽和伴随胆碱能神经再支配救援海马依赖性学习和记忆障碍引起的胆碱能神经去神经支配？“新的”胆碱能纤维是否有功能，它们是否导致M1 mAChR功能，mLTD和学习的拯救？A有吗在胆碱能变性动物中的蓄积直接干扰mAChR信号传导、mLTD诱导/表达和交感神经发芽？这些研究的结果有望证实交感神经发芽在胆碱能变性期间维持海马功能的有益作用，从而为治疗衰老和AD中的认知下降提供新的治疗靶点。 公共卫生相关性：本研究采用胆碱能变性动物模型，探讨内源性刺激的修复机制对海马依赖性学习和突触可塑性的影响。我们预计，这项研究的结果将导致开发新的治疗靶点，用于治疗年龄和疾病相关的记忆丧失。

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. PUBLIC HEALTH RELEVANCE: This study uses an animal model of cholinergic degeneration to investigate the impact of an endogenously stimulated repair mechanism on hippocampal dependent learning and synaptic plasticity. We anticipate that the results from this study will lead to the development of novel therapeutic targets for the treatment of age and disease related memory loss.