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

项目摘要 去甲肾上腺素能(NA)从蓝斑(LC)传入海马区，是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语境恐惧所必需的 行为。齿状回(DG)含有最高的NA含量、最大的NA纤维密度和最大 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。有一部丰富的文献可以追溯到20世纪80年代中期的S，表现出一种批评 β-AR在促进DG突触LTP和LTD诱导中的作用取决于 经验。这种高度的可塑性与高度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的药物阻断而被阻止。重要的是，女性的LC 更大的体积，LC神经元有更大的树突，在发情前期，当血浆雌二醇水平 最高时，NA神经元活性降低。 LC是阿尔茨海默病(AD)中第一个受损的脑区，原因是高密度脂蛋白的积聚。 磷酸化tau(p-tau)。这种病理的后果被大大低估了，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TgF344-AD大鼠模型 在LC中有显著的p-tau积聚，在海马区NA轴突丢失，这使得对LC的详细研究成为可能 NA系统功能障碍对海马区突触传递和学习记忆的影响。显然，识别 防止p-tau积累和LC损伤的策略至关重要。翻译后修饰，O- GlcN酰化，已被证明正是通过与关键丝氨酸残基的磷酸化竞争来实现这一点 在p-tau上导致了它的积累。利用脑片电生理学，我们报告了病理上的增高。 LTP在齿状回的内侧穿支路突触先于CA1突触。在最近的数据中，我们 在药物激活β-AR后，发现内侧穿支路径突触的高度增强。 在NA纤维丢失的情况下，β-AR功能的这种上调可能会导致LTP和掩膜的增加 疾病早期学习和记忆的缺陷。目前的提案将检验这一假设 阿尔茨海默病大鼠海马区去甲肾上腺素能功能受损与Lc-NA细胞兴奋性异常有关 进行性p-tau蓄积和NA失神经，这两种情况在卵巢切除后都会更严重 雌性，受O-GlcN酰化保护。我们将在海马区结合使用电生理学和 蓝斑、海马区依赖行为、药理学、生化和O-GlcNAc生物学测试 这个创新的假说。结果将为LC损伤在AD中的作用提供新的线索，并将奠定基础 致力于针对LC和O-GlcN酰化的治疗策略。

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.