Consequences of Noradrenergic Degeneration in the Novel TgF344-AD Rat Model

项目摘要 去甲肾上腺素能（NA）输入到海马的蓝斑（LC），NA神经支配的唯一供应者， 前脑是获得和巩固空间学习和记忆以及情境恐惧所必需的 行为齿状回（DG）的NA含量最高，NA纤维密度最大， β1-和β2-肾上腺素能受体（AR）在海马结构中的表达，与DG是一种 LC调制控制的关键区域。有丰富的文献可以追溯到20世纪80年代中期， β-AR在DG突触上促进LTP和LTD诱导中的作用取决于 体验.这种增强的可塑性与增强的学习和记忆同时发生，两者都是 通过NA神经支配的丧失或β-AR的药理学阻断来预防。重要的是，女性的LC 体积越大，LC神经元具有越多的树突，并且在动情前期，当血浆雌二醇水平 最高，NA神经元活性降低。 LC是阿尔茨海默病（AD）中受损的第一个脑区域，由于超- 磷酸化tau（p-tau）。这种病理学的后果被大大低估，因为转基因AD 小鼠模型不能概括人类疾病的这一特征。幸运的是，新的TgF 344-AD大鼠模型 LC中有显着的p-tau积聚，海马中有NA轴突丢失，允许对LC进行详细研究 NA系统功能障碍对海马突触传递和学习记忆的影响。很明显， 防止p-tau积累和LC损伤的策略是至关重要的。翻译后修饰，O- GlcNAc酰化，已被证明是通过与关键丝氨酸残基的磷酸化竞争来实现的 p-tau蛋白上，导致它的积累使用脑切片电生理学，我们报告了病理性增强 在两种性别中，齿状回内侧穿通路径突触的LTP均先于CA 1突触。在最近的数据中，我们 发现β-AR药理学激活后内侧穿通通路突触增强。 在NA纤维缺失的背景下，β-AR功能的上调可能会导致LTP升高，并掩盖了 疾病早期的学习和记忆缺陷。目前的提案将检验以下假设： AD中海马去甲肾上腺素能功能通过LC-NA细胞的异常兴奋性受损， 进行性p-tau积累和通过NA去神经，这两种情况在卵巢切除后都会更糟。 雌性并通过O-GlcNAc化保护。我们将结合海马体的电生理学， 蓝斑、海马依赖性行为、药理学、生物化学和O-GlcNAc生物学来测试 这个创新的假设。这些结果将为LC损伤在AD中的作用提供新的线索， 致力于靶向LC和可能的O-GlcNAc化的治疗策略。

Project Summary Noradrenergic (NA) input to hippocampus from locus coeruleus (LC), the sole supplier of NA innervation to forebrain, is required for acquisition and consolidation of spatial learning and memory and contextual fear behavior. The dentate gyrus (DG) contains the highest NA content, greatest NA fiber density, and largest expression of β1-and β2-adrenergic receptors (ARs) in the hippocampal formation, consistent with DG being a key region of modulatory control by LC. There is a rich literature dating back to the mid 1980’s showing a critical role for β-ARs in facilitating induction of both LTP and LTD at DG synapses depending upon the saliency of the experience. This heightened plasticity occurs simultaneous with heightened learning and memory, and both are prevented by loss of NA innervation or pharmacological blockade of β-ARs. Importantly, the LC in females has a larger volume, LC neurons have greater dendritic arbors, and at proestrus, when plasma estradiol levels are the highest, NA neuronal activity is decreased. The LC is the first brain region damaged in Alzheimer’s disease (AD), due to accumulation of hyper- phosphorylated tau (p-tau). The consequence of this pathology is greatly under-appreciated since transgenic AD mouse models do not recapitulate this feature of human disease. Fortunately, the novel TgF344-AD rat model has significant p-tau accumulation in LC and NA axon loss in hippocampus, permitting detailed studies of LC and NA system dysfunction on hippocampal synaptic transmission and learning and memory. Clearly, identifying strategies to prevent p-tau accumulation and LC damage is critical. The post-translational modification, O- GlcNAcylation, has been shown to do just this through competition with phosphorylation at key serine residues on p-tau that cause its accumulation. Using brain slice electrophysiology, we reported pathologically heightened LTP at medial perforant path synapses in dentate gyrus prior to CA1 synapses in both sexes. In recent data, we find heightened potentiation at medial perforant path synapses following pharmacological activation of β-ARs. This upregulation of β-AR function in the context NA fiber loss likely drives the heightened LTP and masks deficits in learning and memory early in the disease. The current proposal will test the hypothesis that hippocampal noradrenergic function in AD is impaired via aberrant excitability of LC-NA cells caused by progressive p-tau accumulation and through NA denervation, both of which will be worse in ovariectomized females and protected by O-GlcNAcylation. We will use a combination of electrophysiology in hippocampus and locus coeruleus, hippocampus-dependent behavior, pharmacology, biochemistry, and O-GlcNAc biology to test this innovative hypothesis. Outcomes will shed new light on the role of LC damage in AD, and will lay the ground work for therapeutic strategies targeting the LC and perhaps O-GlcNAcylation.