O-GlcNAcylation and Hippocampal Synaptic Plasticity

描述（由申请人提供）：在基础条件下，大部分葡萄糖通过糖酵解途径代谢，但2- 4%通过己糖胺生物合成途径（HBP）代谢。HBP修饰葡萄糖产生o -连接的n -乙酰氨基葡萄糖（O-GlcNAc）片段，该片段可以在高动态和可逆的反应中添加到蛋白质的丝氨酸/苏氨酸残基上。当葡萄糖水平过高时，通过HBP的通量增加，这可导致o - glcn酰化蛋白的病理性增加。两种酶，O-GlcNAc转移酶（OGT）和O-GlcNAcase分别负责在蛋白质的丝氨酸/苏氨酸残基上添加和去除O-GlcNAc片段。海马神经元中O-GlcNAc转移酶（OGT）和O- glcnacase在前脑的表达最高。CA3-CA1突触效能的长期变化是海马依赖性学习的基础。海马中OGT和O-GlcNAcase的高表达表明，该脑区正常的突触功能是由突触蛋白的O-GlcNAc转换调节的。然而，对于o - glcn酰化如何调节突触功能知之甚少。此外，O-GlcNAc在突触蛋白上的异常添加可能会干扰突触表达记忆加工所需的长期可塑性的能力，并可能解释已知在糖尿病动物模型中发生的海马突触功能和学习缺陷，其中O-GlcNAc在病理性上升高。到目前为止，还没有研究调查在生理或病理条件下o - glcn酰化对记忆形成的影响。在最近的研究中，我们发现OGT和O-GlcNAcase具有张力活性，并双向调节基础突触传递的强度，这表明通过HBP的自然通量决定了回路的兴奋性水平。此外，我们发现o - glcn酰化的增加限制了突触表达正常LTP的能力，而对LTD没有影响。在本研究中，我们将研究介导o - glcnac酰化升高引起的突触抑制的细胞和分子机制，并确定o - glcnac酰化的慢性升高是否会导致突触功能障碍和学习缺陷。因此，成功证明o - glcn酰化在调节突触传递和可塑性中的生理作用可能是学习和记忆领域的下一个重大发现。这些结果将开启一个新的研究领域，旨在了解在生理和病理条件下由HBP引起的葡萄糖代谢波动如何直接影响突触功能。

DESCRIPTION (provided by applicant): Under basal conditions, the majority of glucose is metabolized through the glycolytic pathway, but 2-4 % is metabolized via the hexosamine biosynthetic pathway (HBP). The HBP modifies glucose to produce an O-linked N-acetylglucosamine (O-GlcNAc) moiety that can be added to serine/threonine residues of proteins in a highly dynamic and reversible reaction. Flux through the HBP is increased when glucose levels are in excess, which can lead to a pathological increase of O-GlcNAcylated proteins. Two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase are responsible for adding and removing, respectively, the O-GlcNAc moiety to serine/threonine residues in proteins. Hippocampal neurons have the highest expression of O- GlcNAc transferase (OGT) and O-GlcNAcase in forebrain. Long-term changes in the efficacy of CA3-CA1 synapses underlie hippocampal dependent learning. The high expression of OGT and O-GlcNAcase in hippocampus suggests that normal synaptic function in this brain region is modulated by O-GlcNAc turnover of synaptic proteins. However little to nothing is known regarding how O-GlcNAcylation modulates synaptic function. Furthermore, the possibility exists that abnormal addition of O-GlcNAc on synaptic proteins could interfere with the ability of synapses to express long-term plasticity required for memory processing and could explain deficits in hippocampal synaptic function and learning known to occur in animal models of diabetes, where O-GlcNAcylation is pathologically elevated. No study to date has investigated the effects of O-GlcNAcylation on memory formation, either under physiological or pathological conditions. In recent studies, we find that OGT and O-GlcNAcase are tonically active and bidirectionally modulate the strength of basal synaptic transmission, suggesting the natural flux through the HBP sets the level of excitability in the circuit. Furthermore, we find that an increase in O-GlcNAcylation limits the ability of synapses to express normal LTP, with no effect on LTD. In this proposal we will investigate the cellular and molecular mechanisms mediating the synaptic depression induced by increased O-GlcNAcylation and determine whether chronic increases in O-GlcNAcylation causes synaptic dysfunction and learning deficits. Thus, the successful demonstration of a physiological role of O-GlcNAcylation in modulating synaptic transmission and plasticity could be the next major discovery in the field of learning and memory. The results obtained will launch a new area of investigation aimed at understanding how fluctuations in glucose metabolism by the HBP can directly affect synaptic function in physiological and pathological conditions.