Muscarinic receptor induced LTD in rat hippocampus

描述(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的增龄性变性和淀粉样β蛋白(A？)在AD时会大大加速，从而导致认知能力下降。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？的毒性非常敏感，而M受体(MAChR)功能的缺陷，特别是M1和M3受体的缺陷，导致淀粉样前体蛋白(APP)的淀粉样变性过程增加。然而，尽管A？以及胆碱能系统，关于它们精确相互作用的机制理解还远远不清楚。重要的是，体内应用M1mAChR激动剂可降低A？在AD患者的脑脊液和AD小鼠模型中，强调了在衰老和AD中维持M1受体功能的重要性。在啮齿动物模型中，胆碱能变性刺激了显著的神经元重排，其中来自颈上神经节的去甲肾上腺素能交感神经纤维发芽进入海马区和皮质的失神经区域。重要的是，在AD患者的海马区已经证实了交感神经的萌发，并在初步研究中得到了证实。在上一个资金周期中，我们发现了海马区“新的”胆碱能纤维的萌发，这完全依赖于来自SCG的交感去甲肾上腺素能纤维的萌发。这些新纤维的出现与在CA3-CA1突触拯救依赖M1受体的LTD有关。这一发现表明，在与年龄和疾病相关的胆碱能变性过程中，存在一种内源性“修复”机制，以维持M1受体的功能和突触的可塑性。这一发现可以为评估胆碱能变性对海马区依赖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AD患者在疾病早期观察到的胆碱能活动增加的原因。在这次竞争性更新中，我们将使用包括行为分析、脑片电生理学、生物化学、免疫组织化学和共聚焦成像在内的多方面方法来解决以下新问题：海马交感神经萌发和伴随的胆碱能神经再支配是否能挽救由胆碱能神经支配导致的海马依赖学习和记忆障碍？这些“新的”胆碱能纤维有功能吗？它们能挽救m1mAChR功能、mLTD和学习吗？A有吗？胆碱能变性动物体内的蓄积直接干扰mAChR信号、mLTD的诱导/表达和交感神经的萌发？这些研究结果有望证实交感神经萌发在胆碱能变性过程中维持海马区功能的有益作用，从而为治疗老年性和阿尔茨海默病的认知衰退提供新的治疗靶点。

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.